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Definitive chemoradiotherapy is one of the treatment options for locally advanced esophageal cancer with curative intent. Esophagitis and pharyngitis are well-known adverse events that occur during chemoradiotherapy, but gastric mucosal injury has been less frequently reported compared to mucositis. Importantly, gastric mucosal injury is not well known, hard to manage, and sometimes fatal. Hence, we examined the clinical characteristics and the incidence of gastric mucosal injury after CRT for esophageal cancer. The medical records of patients who received definitive chemoradiotherapy combined with 5-fluorouracil and cisplatin for stage II/III (nonT4) esophageal squamous cell carcinoma from January 2001 to December 2010 at our institute were reviewed retrospectively. We investigated 256 patients in whom, data for endoscopic abdomen examinations were both before and after CRT were available. Gastric mucosal damage was observed in 90 patients (35%) (grade 1/2/3 = 69/18/3). One of the possible risk factors identified in this study was the irradiation dose to abdomen. Compared to patients with cervical esophagus–upper thoracic esophagus tumor location, patients with middle thoracic esophagus–abdominal esophagus tumor location were more likely to develop gastric mucosal damage, although there was no statistically significant difference. It is important to consider gastric mucosal injury in patients who receive CRT, particularly when the irradiation field includes stomach.

Perirectal hyaluronate gel injection (HGI) appears to be a promising technique for healthy tissue dose sparing in pelvic radiotherapy. In this analysis, we report our initial experience of HGI in gynecologic brachytherapy, focusing on its safety and effectiveness for dose reduction to the rectum. Between July 2013 and May 2014, 36 patients received HGI for primary/salvage gynecologic brachytherapy. Dosimetric effect analysis was based on pre- and post-HGI computed tomography dataset registration with corresponding dose–volume histogram evaluation. The maximum dose to the most exposed 0.1 cm3 (D0.1cm3) and 2.0 cm3 (D2.0cm3) were used as index values for rectum and bladder dose evaluation. The dose indexes for target volume (TV) coverage were TV D90/V100. In all cases, HGI was well tolerated, with no acute or late adverse events documented at a median follow-up of 220 days (range, 18–1046 days). Rectum D2.0cm3 and D0.1cm3 were significantly decreased by HGI (P < 0.001 and P = 0.003, respectively), with no significant impact on dosimetric parameters of bladder and TV coverage. Factors correlating negatively with the dosimetric effect of HGI were an increasing number of interstitial catheters (P = 0.003) as well as Lcranial100% (P = 0.014) and Lcranial80% (P = 0.001) [i.e. the length from the anal verge to the most cranial point at which the 100% and 80% isodose lines, respectively, crossed the rectum]. The concept of HGI for gynecologic brachytherapy is plausible, and our initial experience indicates it to be an effective technique for rectal dose reduction in radiotherapy of intrapelvic tumours.

Objective: To retrospectively investigate the treatment outcomes of external beam radiotherapy with androgen deprivation therapy (ADT) in high-risk prostate cancer in three radiotherapy dose groups. Methods: Between 1998 and 2013, patients with high-risk prostate cancer underwent three-dimensional conformal radiotherapy or intensity-modulated radiotherapy of 66 Gy, 72 Gy, or 78 Gy with ADT. Prostate-specific antigen (PSA) relapse was defined using the Phoenix definition. PSA relapse-free survival (PRFS) was evaluated in each radiotherapy dose group. Moreover, high-risk patients were divided into H-1 (patients with multiple high-risk factors) and H-2 (patients with a single high-risk factor) as risk subgroups. Results: Two hundred and eighty-nine patients with a median follow-up period of 77.3 months were analyzed in this study. The median duration of ADT was 10.1 months. Age, Gleason score, T stage, and radiotherapy dose influenced PRFS with statistical significance both in univariate and multivariate analyses. The 4-year PRFS rates in Group-66 Gy, Group-72 Gy and Group-78 Gy were 72.7%, 81.6% and 90.3%, respectively. PRFS rates in the H-1 subgroup differed with statistical significance with an increasing radiotherapy dose having a more favorable PRFS, while PRFS rates in H-2 subgroup did not differ with increase in radiotherapy dose. Conclusion: Dose escalation for high-risk prostate cancer in combination with ADT improved PRFS. PRFS for patients in the H-1 subgroup was poor, but dose escalation in those patients was beneficial, while dose escalation in the H-2 subgroup was not proven to be effective for improving PRFS. Keywords: Prostate cancer, External beam radiotherapy, Dose escalation, Biochemical control

To perform safe implant treatment, the anatomical structure and bone quality at implant placement sites are evaluated based on a patient's computerized tomography (CT) data, but there is no definite method to determine placement sites and the appropriate number of implants. The objective of this study was to investigate the influence of the number and arrangement of implants on the stress distribution in 3-unit posterior fixed partial dentures for the posterior mandible by mechanical analysis using the finite element method. Three-dimensional finite element analysis models were constructed from the CT data of a patient with missing mandibular teeth (Nos. 35, 36, 37). Implant placement was simulated under various conditions. Superstructures were connected and fixed with a titanium frame. As the loading conditions, 400 N vertical and lateral loads (45° on the lingual side and 45° on the buccal side) were applied to the upper areas of Nos. 35, 36, and 37, and the stress distribution and frame displacement were evaluated. When a vertical force was applied, no difference of the von Mises stress was noted among the 5 experimental conditions. When lateral force was applied from the lingual and buccal sides at 45°, the stress was higher than that induced by vertical force under all conditions, and it was especially high under mesial and distal cantilever conditions. When displacement of the titanium frame was measured, the displacement caused by lateral force was greater than that due to vertical force. In addition, comparison between long and short distal cantilever bridges revealed that displacement of the titanium frame tended to be smaller when the short cantilever was used. These findings suggested that the stress on peri-implant tissues and displacement of the titanium frame vary depending on the configuration and number of implants, with greater stress and more marked displacement of the titanium frame being induced by lateral force when the number of implants is reduced and a cantilever bridge is selected.

[Background] In patients with node-negative (N0), hormone receptor-positive, human epidermal growth factor receptor (HER2) -negative (luminal) breast cancer, the impact of lymphatic invasion (ly) on the prognosis remains to be clarified. [Methods] Among 3,158 patients with primary breast cancers who underwent surgery in our institute from January 2007 to December 2009, we analyzed 1027 N0 luminal invasive breast cancers without preoperative systemic therapy. The luminal breast cancer was defined as hormone receptor-positive (ER of ≥ 10% or PgR of ≥ 10%) and HER2-negative (immunohistochemistry: 0, 1+ or FISH: ratio < 2.0) cancer in the postoperative pathological specimen. ly was defined as positive when cancer cell nests were detected within the lymph duct in the whole specimen. N0 was confirmed pathologically by the sentinel lymph node biopsy in all the patients. The Fisher's exact test was used for comparison between different categories. The distant recurrence rate (DRR) was analyzed using the Kaplan-Meier method and the log-rank test. For multivariate analysis, Cox's regression analysis was performed. [Results] The median follow-up period was 103.8 months (range: 5.6-128.8). Recurrence with distant metastasis occurred in 26 patients (2.5%). There were 5 (0.7%) deaths related to breast cancer. ly was detected in 240 patients (23.4%). In the ly-positive group, the tumor size was larger (p = 0.007), and the nuclear grade (NG) was higher (p < 0.001) than in the ly-negative group. Postoperative endocrine therapy (p < 0.001) and postoperative chemotherapy (p < 0.001) were more frequently employed for patients with ly-positive tumor. The univariate analysis showed that ly positivity (p < 0.001), large tumor size (p < 0.001), high NG (p < 0.001), PgR negativity (p = 0.002) and the history of adjuvant chemotherapy (p < 0.001) were associated with high DRR. In the multivariate analysis, large tumor size (p = 0.007) and PgR negativity (p = 0.015) remained significant. Although positive ly had a risk ratio of 2.2, it was not an independent risk factor.When restricted to T1 tumor (n = 899), the aforementioned factors still showed prognostic value in the univariate analysis, among which ly positivity (p = 0.004)remained significant together with PgR negativity (p = 0.047)in themultivariate analysis.The 8-year DRR was very favorable (0.8%) in patients with ly-negative T1N0 tumor while it was modest (6.6%) in patients with ly-positive T1N0 tumor (p < 0.001). Only 1.3% of the patients had received adjuvant chemotherapy in the ly-negative group while 27% of the patients had in the ly-positive group. [Conclusion] Lymphatic invasion was associated with higher DRR although it was not independent in the multivariate analysis among patients with N0 luminal breast cancer. When restricted to patients with T1N0 luminal breast cancer, the presence of ly was independently associated with higher risk of distant recurrence. It suggests that the assessment of ly is clinically more relevant when considering treatment options for small luminal breast cancer. Citation Format: Abe T, Ito Y, Fukada I, Shibayama T, Ono M, Kobayashi T, Kobayashi K, Takahashi S, Horii R, Akiyama F, Iwase T, Ueno T, Ohno S. Lymphatic invasion is an independent risk factor in patients with small node-negative luminal breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-29.

Background: Docetaxel + Trastuzumab (H) + Pertuzumab (P) provided progression-free survival (PFS) and overall survival (OS) benefits in HER2-positive advanced or metastatic breast cancer (AMBC) in the CLEOPATRA study as a first-line therapy. However, long-term administration of docetaxel at a dose of 75 mg/m2 every 3 weeks in AMBC patients (pts) is difficult due to the toxicities. Eribulin mesylate (E) is a well-tolerated microtubule inhibitor, and we have reported the efficacy and safety of EHP regimen as first- and second-line therapy for AMBC in a multicenter, phase II study (JBCRG-M03/UMIN000012232). In this M06 study, we address the clinical question as to which is the better chemotherapy partner for HP as first line regimen, in terms of efficacy, toxicity and QOL. Methods: JBCRG-M06 is a multicenter open-label randomized phase III study for HER2-positive AMBC pts who have received no prior chemotherapy except for the HER2- Antibody-Drug Conjugate (ADC). Pts will be randomized 1:1 to E (1.4mg/m2 on day 1 and 8) + H (8 mg/kg loading dose followed by 6 mg/kg) +P (840 mg loading dose followed by 420 mg) q3wks or standard taxanes (docetaxel 75mg/m2 on day1 or paclitaxel 80mg/m2 on day 1, 8 and 15) + HP q3wks. Stratification factors for randomization are; presence of visceral metastases, number of prior taxanes on perioperative adjuvant treatment, and treatment with prior anti-HER2-ADC. Primary endpoint is PFS and secondary endpoints include overall response rate, duration of response, OS, patient-reported outcomes (PRO) relating to QOL and peripheral neuropathy, new-metastases free survival, and safety. Translational research to search for biomarker for individual precision therapy will be performed. Main eligibility criteria are as follows: pts with HER2-positive AMBC, female aged 20-70 years old, ECOG PS of 0-1, LVEF ≥ 50% at baseline and adequate organ function. Pts who had progressive MBC within 6 months after the end of primary adjuvant systemic chemotherapy are excluded. The sample size was calculated by type1 error (2-sided) of 0.05 and 80% power to estimate the noninferiority margin 1.33 with an expected median PFS of 14.2 months. The target number of pts is 480 recruited over the duration of 3-years. The first patient in was achieved on August 2017. (ClinicalTrials.gov Identifier:NCT03264547). Citation Format: Masuda N, Yamashita T, Saji S, Araki K, Ito Y, Takano T, Takahashi M, Tsurutani J, Koizumi K, Kitada M, Kojima Y, Sagara Y, Tada H, Iwasa T, Kadoya T, Iwatani T, Hasegawa H, Morita S, Ohno S. A phase III trial to compare eribulin mesylate + trastuzumab (H) + pertuzumab (P) with paclitaxel or docetaxel + HP for HER2-positive advanced or metastatic breast cancer (JBCRG-M06/ EMERALD) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-05.

Background: Two randomized controlled trials comparing the efficacy of oral tegafur-uracil (UFT) (2 years) with that of classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (6 courses) were conducted in patients with resected early breast cancer. UFT is an oral fluoropyrimidine that combines tegafur, a prodrug of 5-fluorouracil, with uracil in a 1:4 molar ratio. One study was the N-SAS-BC01 trial (Watanabe et al, J Clin Oncol 2009), which was conducted in patients with high-risk node-negative breast cancer (n=733). The other was the CUBC trial (Park et al, Br J Cancer 2009), which was performed in patients with node-positive breast cancer (n=377). We reported the pooled analysis of these two randomized control trials using individual patient data (Ohashi et al, Breast Cancer Res Treat 2010). This pooled analysis showed that UFT was non-inferior to CMF in terms of inhibiting recurrence of estrogen receptor (ER)-positive early breast cancer. In addition, an exploratory subgroup analysis showed that UFT may be more effective in ER-positive patients who were 50 years or older. The present study was conducted to investigate the long-term efficacy of UFT or CMF in patients with early breast cancer. Methods: Long-term follow-up data for disease recurrence and survival were collected. Hazard ratios (HR) were determined using the Cox model stratified by study and adjusted for clinical characteristics, namely age, tumor size, nodal status, histological type, ER, and progesterone receptor (PgR). Survival curves were estimated by the Kaplan-Meier method. Hochberg multiplicity adjustment was applied in the previous pooled analysis, and non-inferiority of UFT versus CMF was shown in terms of relapse-free survival (RFS) in the ER-positive patient group. We investigated the non-inferiority of UFT in the same patient group with updated data. Restricted mean survival time (RMST) was calculated to consider the relative efficacy of UFT. This study is registered with JapicCTI-163321. Results: In total, 1,057 patients were analyzed (CMF, n=528; UFT n=529). The median follow-up time was 11.1 years (12.1 years in the N-SAS-BC 01 trial and 8.3 years in the CUBC trial). Table 1 shows the 10-year RFS and overall survival (OS) in all patients and ER-positive patients. The difference in RMST between arms at 20 years in terms of RFS was -2.7 months in all patients and 3.4 months in ER-positive patients. Table 2 shows the HR for RFS according to ER status and age. UFT (%)CMF (%)UFT to CMF; HR (95% CI)10-year RFSall patients74.477.11.02 (0.81–1.30)ER-positive patients75.075.10.91 (0.66–1.27)10-year OSall patients86.886.90.98 (0.72–1.34)ER-positive patients89.987.90.86 (0.54–1.37) Age Conclusion: This study shows that UFT was shown to be non-inferior to CMF in terms of RFS in ER-positive early breast cancer. This result is similar to that of the previous pooled analysis. Sponsor: Taiho Pharmaceutical Co., LTD Citation Format: Yonemori K, Ohsumi S, Takao S, Tokuda Y, Ito Y, Nakagami K, Takahashi M, Yoshidome K, Nakayama T, Yamaguchi Y, Ohashi Y, Inaji H, Watanabe T. Long-term follow-up of two randomized controlled trials (N-SAS-BC01 trial and CUBC trial) comparing oral tegafur-uracil (UFT) versus classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant therapy in early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-09.

Epstein-Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer1,2. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification1,2. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms3. Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF14-7, while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.

Background/aim When possible, surgical resection is recommended for local recurrence after resection of colorectal cancer. In unresectable cases, chemotherapy is usually indicated, although the success of chemoradiotherapy (CRT) in this setting is unclear. Patients and methods We retrospectively reviewed the treatment outcomes of 18 patients who received CRT for unresectable local recurrence after radical colorectal cancer surgery at our hospital between January 2000 and May 2016. Results Of these 18 patients, three experienced complete response and four experienced partial response, resulting in a 39% overall response. With a median follow-up time of 42 months, the 5-year progression-free survival and overall survival were 34.8% and 54.4%, respectively; associated with a median local failure-free survival time of 40.9 months. Two of the three patients that underwent CRT remained local failure free for 5 years. Conclusion CRT for local recurrence of rectal cancer without distant metastasis produces similar overall survival rates and local control as conventional surgical resection.

Background The family members of terminally ill patients are often requested to make difficult surrogate decisions during palliative care. This study sought to clarify the appropriate communication style for physicians as perceived by family members confronting difficult surrogate decision-making. Methods This experimental psychological study used scripted videos. In the videos, the physician described treatment options including continuous deep sedation to the family members of patients with cancer and terminal delirium using an autonomous or paternalistic style. Medical professionals with clinical experience in oncology were randomly assigned to either group viewing the videos. The primary outcomes were physician compassion, decisional conflict and emotion scores. We also evaluated the communication style preference. Results In total, 251 participants completed this study. Although participants in both groups reported high physician compassion, participants in the autonomous style group reported lower compassion scores (reflecting higher physician compassion) (mean 15.0 vs. 17.3, P = 0.050), lower decisional conflicts scores (51.1 vs. 56.8, P = 0.002) and comparable emotions compared with those in the paternalistic style group. Seventy-six percent of participants preferred the autonomous style. Conclusions Regarding difficult surrogate decision-making, the autonomous style might be more appropriate than the paternalistic style. However, various factors, such as family members' communication style preferences, family members' values, physician-family relationships and ethnic cultures, should be considered.

Visual tracking of complex objects has been studied extensively in the field of robot vision, visual servoing, and surveillance. Detection of reliable low level visual features has been crucial, in the literature, for the stability of tracking in cluttered scene. However, using only low level features for tracking tends to be illusory for practical vision systems, and the selection of reliable visual features is still an important unsolved issue. In recent studies it has been stressed the importance of high-level features in guiding control for long-duration tracking (Matsugu et al., 2006; Li et al., 2007; Yang et al., 2007), computer vision (Sun & Fisher, 2003), and visual search (Lee et al., 2005). Recent cognitive neuro-psychological as well as brain imaging studies also revealed a role of top-down attention in visual search task in human vision system (Patel & Sathian, 2000; Hopfinger et al., 2000; Corbetta & Shulman, 2002; Navalpakkam & Itti, 2006). In this chapter, we present a new object tracking vision system that incorporates both top-down and bottom-up attention processes. Tracking a specific object using both low-level and high-level features is not new and was previously studied (Isard & Blake, 1998) in a stochastic framework. The proposed active vision system in this chapter is task-oriented and tracks a specific object (i.e., person). The tracking process is initiated by the top-down process which is activated by robust object detection module (Matsugu & Cardon, 2004; Matsugu et al., 2004). Subsequent feature selection for tracking involves simultaneous

Background Febrile neutropenia (FN) is a frequent complication in immunocompromised patients. However, causative microorganisms are detected in only 10% of patients. This study aimed to detect the microorganisms that cause FN using next-generation sequencing (NGS) to identify the genome derived from pathogenic microorganisms in the bloodstream. Here, we implemented a metagenomic approach to comprehensively analyze microorganisms present in clinical samples from patients with FN. Methods FN is defined as a neutrophil count, Metagenomic next-generation sequencing was used to diagnose pathogens in 17% of pediatric patients with febrile neutropenia with negative blood culture test results. Metagenomic blood analysis suggested translocation of the human microbiota into the bloodstream in neutropenia.

The use of sentinel node biopsy (SNB) following neoadjuvant chemotherapy (NAC) for patients with cN1 breast cancer is controversial. Improvements of negative predictive value (NPV) by axillary ultrasound (AUS), which corresponds to the accurate prediction rate of node-negative status after NAC, would lead to decreased FNR of SNB following NAC. In this study, we retrospectively investigated the accurate prediction rate of NPV by AUS after NAC in patients with cytologically node-positive breast cancer treated between January 2012 and December 2016. Of 279 eligible patients, the NPV was 49.2% in all patients, but varied significantly by tumor subtype (p p = 0.0003). Of the 23 patients with clinically node negative (ycN0) by AUS and clinical complete response in primary lesion by MRI, the NPV was 100% in patients with HR±/HER2+ or HR−/HER2− breast cancer. In conclusion, regarding FNR reduction post-NAC, it will be of clinical value to take tumor subtype and primary tumor response using MRI into account to identify patients for SNB after NAC.

Objectives: This study aimed to analyse the effects of rescue breath and chest compression combinations in bystander cardiopulmonary resuscitation (BCPR) with and without dispatch-assisted CPR (DA) on the outcomes between unwitnessed and bystander-witnessed out-of-hospital cardiac arrest (OHCA).Design and Settings: This retrospective study analysed the prospectively collected data of 212,003 unwitnessed and 117,920 bystander-witnessed OHCA cases between 2014 and 2016 in Japan, with BCPR classification based on two clinical components (DA provision [with or without DA] and combination of breaths and compressions [standard or compression-only]).Main outcome measures: Neurologically favourable outcome at 1 monthResults: In univariate analysis, unwitnessed cases had no significant association of BCPR with the overall neurologically favourable outcome (provided vs not provided, 0.65% [686/106,152] vs 0.66% [694/105,851]) compared with bystander-witnessed cases (5.6% [3,538/62,814] vs 3.5% [1,911/55,106]). After BCPR classification by two clinical components, the outcome of unwitnessed cases was improved by standard BCPR with DA (0.88% [69/7,807], adjusted OR; 95% CI, 1.38; 1.05–1.81) and compression-only (1.04% [161/15,497], 1.49;1.23–1.80) and standard (1.18% [41/3,463], 1.71; 1.21–2.43) BCPR without DA, but not by compression-only BCPR with DA (0.52% [415/79,385], 0.88; 0.76–1.01). According to multivariable logistic regression analysis focusing on the two clinical components only in cases with BCPR, neurologically favourable outcomes were worse in DA provision (0.76; 0.60–0.97) but better in standard BCPR, (1.27; 1.01–1.60) without significant interaction (P = 0.16), in unwitnessed cases. In bystander-witnessed cases, DA provision was associated with better outcomes (1.27; 1.01–1.60), with significant interaction (P = 0.03).Conclusions: Compared with no BCPR, compression-only BCPR with DA does not improve the neurologically favourable outcomes, and standard BCPR without DA is ideal in unwitnessed OHCA cases. Education on standard CPR and chest compression-only CPR as an option should be maintained because numerous OHCA cases are not witnessed by bystanders.

Background Immunosuppression during liver transplantation (LT) enables the prevention and treatment of organ rejection but poses a risk for severe infectious diseases. Immune modulation and antimicrobials affect the plasma microbiome. Thus, determining the impact of immunosuppression on the microbiome may be important to understand immunocompetence, elucidate the source of infection, and predict the risk of infection in LT recipients. We characterized the plasma microbiome of LT recipients at early post-LT and assessed the association between the microbiome and clinical events. Results In this study, 51 patients who received LT at Nagoya University Hospital from 2016 to 2018 were enrolled. Plasma samples were retrospectively collected at the following time points: 1) within a week after LT; 2) 4 ± 1 weeks after LT; 3) 8 ± 1 weeks after LT; and 4) within 2 days after a positive blood culture. A total of 111 plasma samples were analyzed using shotgun next-generation sequencing (NGS) with the PATHDET pipeline. Relative abundance of Anelloviridae, Nocardiaceae, Microbacteriaceae, and Enterobacteriaceae significantly changed during the postoperative period. Microbiome diversity was higher within a week after LT than that at 8 weeks after LT. Antimicrobials were significantly associated with the microbiome of LT recipients. In addition, the proportion of Enterobacteriaceae was significantly increased and the plasma microbiome diversity was significantly lower in patients with acute cellular rejection (ACR) than non-ACR patients. Sequencing reads of bacteria isolated from blood cultures were predominantly identified by NGS in 8 of 16 samples, and human herpesvirus 6 was detected as a causative pathogen in one recipient with severe clinical condition. Conclusions The metagenomic NGS technique has great potential in revealing the plasma microbiome and is useful as a comprehensive diagnostic procedure in clinical settings. Temporal dynamics of specific microorganisms may be used as indirect markers for the determination of immunocompetence and ACR in LT recipients.

Background: Many out-of-hospital cardiac arrest cases are unwitnessed. For both unwitnessed and witnessed cases, recent guidelines endorse the dispatcher’s instruction of compression-only cardiopulmonary resuscitation to lay rescuers without previous resuscitation training. This study aimed to investigate the changes in the composition of bystander resuscitation based on the combination of rescue breathing and dispatcher-assisted resuscitation, and the association of the changes in bystander resuscitation content with annual outcome improvement in unwitnessed out-of-hospital cardiac arrest cases.Method: Retrospective analysis of prospective national cohort study in a population-based setting. Out-of-hospital cardiac arrest cases in 2009–2016 (986,760 cases) were reviewed to provide a complete dataset for analyses (941,858 cases). Main outcome was neurologically favorable survival at 1 month.Results: Of the 941,858 cases, the rates of neurologically favorable survival adjusted for prehospital confounders continuously increased annually. When classified into 5 groups according to the contents of resuscitation, the proportions of the dispatcher-assisted compression-only resuscitation group increased annually, whereas the proportions of the other groups decreased. That is, the shift from standard (defined as the combination of chest compressions and rescue breathings) to compression-only bystander resuscitation were observed for both unwitnessed and bystander-witnessed cases. In unwitnessed cases, the survival rate of the dispatcher-assisted compression-only resuscitation group was always lower than that of the no-resuscitation group during the study period. On the other hand, the survival rate of dispatcher-assisted standard resuscitation group exceeded that of the no-resuscitation group at the end of the study period (adjusted odds ratio; 95% confidence intervals (CI), 1.41; 1.02–1.93), and the increase in survival rate was prominent compared to that of the dispatcher-assisted compression-only resuscitation group (adjusted unit odds ratio/year; 95% CI, 1.15; 1.08–1.24 vs. 1.04; 1.00–1.07).Conclusions: The proportions of dispatcher-assisted compression-only resuscitation group increased annually, but its survival rate of the neurologically favorable 1-month did not exceed compared to that of the no-resuscitation group in unwitnessed cases. The dispatcher-assisted compression-only resuscitation did not appear to be an ideal management for unwitnessed out-of-hospital cardiac arrest cases.

Background The Safari study (UMIN 000015168) was a retrospective, multicenter study in which 1072 consecutive cases of estrogen receptor-positive (ER+) advanced breast cancer (ABC) treated using 500 mg fulvestrant were registered. We previously reported the relationship between the patient factors and overall survival (OS) after the diagnosis using the same cases and the same factors for the analysis of time to treatment failure (TTF) in patients with ER + ABC. The current study is an ad-hoc analysis that focused on the relationship between the patient factors and OS after recurrence by adding factors generally associated with OS after recurrence. Methods The OS after recurrence in patients with ER + human epidermal growth factor receptor 2 negative (HER2−) recurrent breast cancer was analyzed via univariate and multivariate analyses with a Cox proportional hazards model. Results A total of 598 cases were used for the analysis of OS after recurrence. Multivariate analysis revealed that favorable OS (median, 6.4 years) was significantly correlated with long time from recurrence to fulvestrant use (≥ 3 years), low nuclear or histological grade (G3 vs. G1), long TTF of initial palliative endocrine therapy (≥ 12 months), and long time to initial palliative chemotherapy (≥ 2 years). Conclusion In patients with ER + HER2 − recurrent breast cancer who received endocrine therapy as the primary palliative treatment, the low proliferation activity of the tumor at the first diagnosis, sensitivity to initial endocrine therapy after the recurrence, and long time to the initiation of chemotherapy might be correlated with the favorable OS after recurrence. Trial registration: University Hospital Medical Information Network: UMIN 000015168, 2014/09/16

Thoracoscopic esophagectomy (TE) is considered the standard surgery for esophageal cancer because of its superiority over open esophagectomy (OE) in terms of short-term outcomes. However, few prospective multicenter studies have evaluated its long-term survival after TE. This study aimed to investigate whether the prognosis for patients with T1bN0M0 esophageal cancer after TE is not inferior to OE using data from the Japan Clinical Oncology Group Study (JCOG0502), a prospective multicenter trial comparing esophagectomy with chemoradiotherapy. Data of patients in JCOG0502 after esophagectomy were used to compare the overall survival (OS) and relapse-free survival (RFS) after OE versus TE. OE or TE was selected at the surgeon’s discretion. A hazard ratio and 95% confidence interval (CI) were calculated via Cox proportional-hazards model. Of the 210 patients who underwent esophagectomy, 109 underwent OE, whereas 101 underwent TE. The 5-year OS was 88.9% after OE and 85.0% after TE. The hazard ratio of TE for OS was 1.53 (95% CI, 0.84–2.78; p = 0.16) and 1.10 (95% CI, 0.52–2.35; p = 0.80) in the univariable and multivariable analyses, respectively. The 5-year RFS was 85.3% after OE and 79.1% after TE. The hazard ratio of TE for RFS was 1.39 (95% CI, 0.81–2.38; p = 0.23) and 0.88 (95% CI, 0.44–1.74; p = 0.70) in the univariable and multivariable analyses, respectively. The prognosis for patients with T1bN0M0 esophageal cancer after TE was not inferior to OE.

Cervical esophageal squamous cell carcinoma (CESCC) is rare, accounting for 5% of all esophageal carcinomas. Several diagnostic and predictive markers have been studied. However, to the best of our knowledge, no biomarker is known to determine patient management except the clinical stage. The present study aimed to evaluate whether human papilloma virus (HPV) infection, epidermal growth factor receptor (EGFR) and its pathway-related gene mutations, known to be sensitive biomarkers of oropharyngeal carcinomas, could be used as biomarkers for the prediction of the prognosis of patients with CESCC. The present retrospective study included patients with CESCC who received chemoradiotherapy or surgery. HPV infection and the genomic status of EGFR, KRAS, BRAF, NRAS and PIK3CA of each tumor sample from patients with CESCC were analyzed by in situ hybridizations (ISH) and PCR methods, respectively. The present study included 33 patients with CESCC (male/female, 29/4; median age, 62 years; age range, 41-86 years; clinical stage I/II/III/IV, 2/6/10/15). The present study detected HPV in one patient (3.0%) by ISH and PCR. Concerning the investigation of EGFR and its pathway-related gene mutations, the present study detected 15.1% of EGFR, 6.0% of NRAS, 3.5% of BRAF, 3.0% of KRAS and 3.0% for PIK3CA mutations, with no significant relationship between any gene mutations and the clinical prognostic factors. The HPV-infected patient did not exhibit any gene mutations. The present study indicated that HPV infection, EGFR and its pathway-related gene mutations rarely exist in patients with CESCC. The relationship between these biomarkers and the prognosis in patients with CESCC is still unclear.

BackgroundSemi-quantitative analysis is used to evaluate the degree of tracer binding to the striatum in dopamine transporter (DaT) single-photon emission computed tomography (SPECT). In DaT SPECT, it is difficult to evaluate the accurate tracer accumulation due to the partial volume effect (PVE). In this study, we propose a novel semi-quantitative approach for measuring the amount of accumulation by examining the approximate image. Using the striatal phantom, we verified the validity of a newly proposed method that can accurately evaluate the tracer accumulations in the caudate and putamen, separately.MethodsThe left and right caudate/putamen regions, and the whole brain region as the background (BG) region were identified in computed tomography (CT) images obtained by SPECT/CT imaging, and the positional information of each region was obtained. The SPECT-like images were generated by assigning assumed accumulation amounts to the left and right caudate/putamen and BG regions based on the positional information. By changing the assumed accumulation amounts assigned to each region, the SPECT-like image, which was approximated to the image obtained by the SPECT imaging, was examined. The accumulation amounts assumed, when the generated SPECT-like image approximated the most to the image actually obtained by the SPECT imaging, were determined as the accumulation amounts in each region. We evaluated the correlation between the count density calculated by the proposed method and the actual count density of 123I solution filled into the striatal phantom, and verified the validity of the proposed method. In addition, the specific binding ratio (SBR) and caudate-putamen ratio (CPR) computed by the proposed method were compared with the theoretical SBR and CPR calculated by the count density of the 123I solution filled into the striatal phantom.ResultsThe count density calculated by the proposed method and the count density of 123I solution filled in the striatal phantom had an extremely strong positive correlation (r=0.997, p < 0.001). The SBRs computed by the proposed method were overestimated. However, the obtained CPRs were very similar to the theoretical CPRs.ConclusionsThe proposed method was able to compute the accurate accumulation amounts in the caudate and putamen, considering the PVE.

OBJECTIVE This is an ancillary study of a multi-institutional randomized non-inferiority phase III trial of accelerated fractionation (AF) versus standard fractionation (SF) radiation therapy for T1-2N0M0 glottic cancer (JCOG0701). Biopsy specimens of tumors from the patients enrolled in the JCOG0701 are collected and the association between clinical outcomes and histopathologic features such as expression of epithelial cell adhesion molecule (EpCAM), p53, and p16 were investigated. METHODS Five slices of undyed slides from biopsy specimens were sent to the National Cancer Center Hospital and all the specimens were assessed for the expression of EpCAM, p53, and p16. The primary objective was to investigate the association between 3-year progression-free survival (PFS) and expression of EpCAM, p53, and p16. RESULTS A total of 88 out of 370 patients were enrolled in this ancillary study. The 3-year PFS for tumors with strong expression of EpCAM was 70.6% (95% CI 43.1%-86.6%), while that of tumors without strong expression of EpCAM was 77.5% (95% CI 65.9%-85.5%) with no remarkable difference between groups (P = .67). Likewise, there was no significant difference in 3-year PFS between tumors regardless of p53 or p16 status. However, in a subgroup analysis for 17 patients with a strong expression of EpCAM, AF showed better 3-year PFS than SF (100% vs 54.5%, P = .07). CONCLUSIONS From the current study, it could not be concluded that EpCAM, p16, and p53 were prognostic factors for early-stage glottic cancer after primary radiation therapy. AF might be an appropriate fractionation for tumors with a strong expression of EpCAM. LEVEL OF EVIDENCE 3 Laryngoscope, 131:1522-1527, 2021.

This retrospective study aimed to evaluate the effect of the antiemetic drug olanzapine(OLZ)on blood sugar levels in patients treated with adjuvant or neoadjuvant chemotherapy(AC: doxorubicin plus cyclophosphamide or CEF: cyclophosphamide plus epirubicin plus fluorouracil) for breast cancer. Here, we evaluated the frequency of diabetes(postprandial blood sugar: PBS≥200 mg/dL)and the change in PBS in 149 patients who were prescribed OLZ between September 2016 and August 2017 at our hospital. No diabetic patients were identified during the observation period(median: 3 cycles of chemotherapy). Among the 95 patients with more than 2 PBS readings, no difference was observed in the incidence of increased PBS, regardless of the diabetic risk, before and after OLZ administration. This study therefore found that the short term use of OLZ as an antiemetic had little effect on PBS, suggesting that it can be used safely during treatment with AC or CEF.

Background: Hepatitis B virus (HBV) is detected in extrahepatic tissues of individuals with HBV infection. Whether nails and hair contain HBV has been unknown. Methods: We examined two patient groups: those with chronic HBV infection alone (n=71), and those with both chronic HBV and hepatitis delta virus (HDV) infections (n=15). HBV DNA in the patients' fingernails and hair were measured by real-time PCR. Hepatitis B surface antigen (HBsAg) of fingernails was evaluated by an enzyme immunoassay. HDV RNA in fingernails was measured by real-time PCR. Immunochemical staining was performed on nails. We used chimeric mice with humanized livers to evaluate the infectivity of nails.Results: Of the 71 pairs of HBV-alone nail and hair samples, 70 (99%) nail and 60 (85%) hair samples were positive for β-actin DNA. Of those 70 nail samples, 65 (93%) were HBV DNA-positive. Of the 60 hair samples, 49 (82%) were HBV DNA-positive. The serum HBV DNA level of the nail HBV DNA-positive patients was significantly higher than that of the nail HBV DNA-negative patients. The hair HBV DNA-positive patients' serum HBV DNA level was significantly higher compared to the hair HBV DNA-negative patients. The nail HBV DNA level was significantly higher than the hair HBV DNA level. The nails and hair HBV DNA levels were correlated (r=0.325, pConclusions: Nails and hair were the reservoir of HBV DNA. Moreover, nails can contain HBsAg, HDV RNA, and HD antigen.

This study investigates the quality indicators (QIs) of medical care that are expected to be introduced to radiotherapy departments in Japan and evaluates whether the QIs reflect the characteristics of the treatment facilities. For this purpose, a questionnaire survey was administered to radiotherapy treatment facilities in Japan. A consensus of early QI candidates was obtained from the panel members. The characteristics identified in the candidate QIs were subdivided into 140 items covering 27 domains of medical-care contents in radiotherapy departments. These 140 items were compiled into a questionnaire, which was administered to 15 treatment facilities in Japan. The primary results indicated that 36 items in five domains are useful QI contents. The secondary findings indicated that the provision of advanced radiotherapy to several patients, the waiting time, and the radiotherapy initiated depend on the manpower of the departmental staff.

Objective To evaluate the safety and efficacy of hypofractionated whole breast irradiation for Asian women after breast-conserving surgery. This is an updated report with 5-year follow-up. Methods and materials Asian women who had invasive breast cancer with clinical tumor size ≤3 cm, pN0-1c and negative inked margins were enrolled. Hypofractionated whole breast irradiation of 42.56 Gy/16 fractions was delivered, and boost irradiation of 10.64 Gy/4 fractions was added when the surgical margin was ≤5 mm. The primary endpoint was the proportion of grade ≥ 2 late adverse reactions within 3 years. Secondary endpoints included early adverse events, overall survival, disease-free survival, ipsilateral breast relapse-free survival, late adverse reactions and cosmetic outcome. Toxicities were evaluated using CTCAE ver3.0. Cosmetic outcomes were assessed using a 4-point scale and CTCAE ver3.0 for hyper/hypopigmentation, breast nipple/areolar deformity and breast volume/deformity. Results Between February 2010 and August 2012, 312 patients were enrolled, and 306 received hypofractionated whole breast irradiation. Median follow-up was 70.5 (range 7.6–88.9) months. The proportion of grade ≥ 2 late adverse reactions within 3 years was 4.3% (90% confidence interval 2.5–6.7%). Grade 2 early adverse events occurred in 38 (12.4%); none had grade 3/4. Five-year overall survival, disease-free survival and ipsilateral breast relapse-free survival were 98.7, 95.4 and 98.0%, respectively. Of the 304 evaluable patients, 29 (9.5%; 95% confidence interval 6.5–13.4%) had grade 2/3 late adverse reactions; none had grade 4/5. At 5 years, 70/289 (24.2%) showed any worsening of breast cosmetic changes. Conclusions Hypofractionated whole breast irradiation is considered a standard treatment for Asian women with margin-negative invasive breast cancer after breast-conserving surgery.

Gene-protein assay (GPA), a combination of immunohistochemistry and dual in situ hybridization, allows simultaneous visualization of HER2 protein and gene on a single slide. We aimed to clarify the clinical significance of HER2 intratumoral heterogeneity (ITH) using GPA. We investigated the relationships between various HER2 ITH indicators and clinical course in 102 patients with HER2-positive breast cancer, treated with neoadjuvant trastuzumab and chemotherapy. Five representative microscopic images were captured from each GPA slide of pre-therapeutic biopsy materials. All evaluable cancer cells in the images were individually assessed for HER2 gene copy number and protein expression. Mean and coefficient of variation (CV) of both gene copy number and protein category were calculated, and each was divided into negative, equivocal, and positive. Based on their combined status, cancer cells were classified into nine types. Pathological complete response (pCR) to neoadjuvant treatments showed positive relationships to mean gene copy number (P < 0.001), mean protein category (P < 0.001), and proportion of gene- and protein-positive tumor cells (P < 0.001) and showed negative relationships to the CV of protein category (P < 0.001) and the proportion of gene-amplified but protein-negative tumor cells (P = 0.002). Two diagnostic models, created by combining clinicopathological factors and ITH indicators, showed excellent potential diagnostic ability for pCR (mean gene copy number and protein category CV; AUC = 0.837, proportion of gene- and protein-positive tumor cells; AUC = 0.831). HER2 ITH quantified by GPA is a potential predictive indicator for efficacy of HER2-targeted treatment.

Objectives Next-generation sequencing has been applied to the investigation of microorganisms in several clinical settings. We investigated the infectious etiologies in respiratory specimens from pediatric patients with unexpected cardiopulmonary deterioration using next-generation sequencing. Design Retrospective, single-center, observational study. Setting Tertiary care, a children's hospital. Subjects The study enrolled a total of 16 pediatric patients with unexpected cardiopulmonary deterioration who were admitted to the PICU. Ten bronchoalveolar lavage fluid and six transtracheal aspirate samples were analyzed. Interventions None. Measurements and main results RNA libraries were prepared from specimens and analyzed using next-generation sequencing. One or more bacterial/viral pathogens were detected in the bronchoalveolar lavage fluid or transtracheal aspirate specimens from 10 patients. Bacterial and viral coinfection was considered in four cases. Compared with the conventional culture and viral antigen test results, an additional six bacterial and four viral pathogens were identified by next-generation sequencing. Conversely, among 18 pathogens identified by the conventional methods, nine pathogens were detected by next-generation sequencing. Candidate pathogens (e.g., coxsackievirus A6 and Chlamydia trachomatis) were detected by next-generation sequencing in four of 10 patients in whom no causative pathogen had been identified by conventional methods. Conclusions Our results suggest that viral and bacterial infections are common triggers in unexpected cardiopulmonary deterioration in pediatric patients. Next-generation sequencing has the potential to contribute to clarification of the etiology of pediatric critical illness.

Background Internal mammary and/or supraclavicular (IM–SC) lymph node (LN) recurrence without distant metastasis (DM) in patients with breast cancer is rare, and there have been few reports on its clinical outcomes. Methods We enrolled 4237 patients with clinical stage I–IIIC breast cancer treated between January 2007 and December 2012. Clinicopathological features of patients with IM–SC LN recurrence and patients with DM were retrospectively reviewed. Results With a median follow-up time 78 (range, 13–125) months after the primary operation, 14 (0.3%) had IM–SC LN recurrence without DM and 274 (6.5%) had DM at the first recurrence among 4237 patients. No statistical differences were found in the baseline characteristics of the primary tumor between the two groups. The 5-year overall survival (OS) rate after recurrence in patients with IM–SC LN recurrence was 51% compared with 27% in patients with DM (P = 0.040). In patients with IM–SC LN recurrence, clinically positive axillary LN at diagnosis and pathologically positive axillary LN at primary surgery were poor prognostic factors for distant disease-free survival (DDFS) (P = 0.004 and 0.007, respectively). Clinical and pathological axillary nodal status at primary surgery was associated with OS (P = 0.011 and 0.001, respectively). Conclusions Patients with IM–SC LN recurrence without DM who had no clinical and pathological axillary LNs involved at primary surgery had a favorable prognosis. A larger validation study is required.

Background: It is unknown whether patients with cytologically proven axillary node-positive breast cancer who achieve axillary pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have comparable prognosis to patients with axillary pathological node-negative disease (pN-) without NAC. Methods: We retrospectively reviewed the data of patients with cytologically proven axillary node-positive disease who received NAC and those with axillary pN- without NAC for control between January 2007 and December 2012. We compared outcomes according to response in the axilla to NAC and between patients with axillary pCR and matched pairs with axillary pN- without NAC using propensity scores. Results: We included 596 patients with node-positive breast cancer who received NAC. The median follow-up period was 64 months. Patients with axillary pCR showed significantly better distant disease-free survival (DDFS) and overall survival (OS) than patients with residual axillary disease (both p &lt, 0.01). There was no significant difference in DDFS and OS between patients with axillary pCR and matched pairs with axillary pN- without NAC. Conclusion: Axillary pCR was associated with improved prognosis. Patients with axillary pCR and matched pairs with axillary pN- without NAC had comparable outcomes. This information will be useful when considering the intensity of follow-up and adjuvant therapy.

Brain MRI provides important information about suspected congenital CMV infection in neonatally underdiagnosed children. This study aimed to describe MRI findings in children in whom congenital CMV infection was not suspected during the neonatal period and was proven retrospectively.We enrolled 31 children referred to the pediatric neurology clinic with neurological symptoms who were proven to have congenital CMV infection based on dried umbilical cord samples. Upon diagnosis, MR and CT images were assessed using the van der Knaap scoring system integrated with additional variables. Two investigators independently assessed all images.The age at diagnosis was12 months in 14, 12-24 months in 11, and24 months in 6 patients. The initial symptom triggering clinic referral was delayed development in 22, seizure in 5, deafness in 3, and hemiplegia in 1 patient. Of the 31 children, 30 had a white matter (WM) abnormality predominant in the deep WM of the parietal lobe (n = 25). Anterior temporal lesions were observed in 21 children. Cortical lesions were observed in 7 children, suggestive of polymicrogyria. No child had cerebellar or brainstem abnormalities. Brain CT was performed in 22 of 31 children, and 11 showed punctate cerebral calcification in the periventricular and/or deep WM.Patients with congenital CMV infection with delayed neurological symptoms show a relatively uniform pattern of parietal-dominant multifocal WM lesions and anterior temporal lesions, with or without polymicrogyria.

Background Chemoradiotherapy is a treatment option for locally advanced pancreatic cancer. However, the efficacy of induction chemotherapy prior to chemoradiotherapy is uncertain. The aim of this randomized, multicentre phase II study is to evaluate the efficacy and safety of chemoradiotherapy with and without induction chemotherapy to determine the significance of induction chemotherapy. Methods Patients with locally advanced pancreatic cancer were randomly assigned to the chemoradiotherapy arm (Arm A) or induction chemotherapy followed by the chemoradiotherapy arm (Arm B). Patients in Arm A underwent radiotherapy with concurrent S-1. Patients in Arm B received induction gemcitabine for 12 weeks, and thereafter, only patients with controlled disease underwent the same chemoradiotherapy as Arm A. After chemoradiotherapy, gemcitabine was continued until disease progression or unacceptable toxicity in both arms. The primary endpoint was overall survival. Results Amongst 102 patients enrolled, 100 were eligible for efficacy assessment. The probability of survival was greater in Arm B in the first 12 months, but the trend was reversed in the following periods (1-year survival 66.7 vs. 69.3%, 2-year survival 36.9 vs. 18.9%). The hazard ratio was 1.255 (95% confidence interval 0.816–1.930) in favour of Arm A. Gastrointestinal toxicity was slightly more frequent and three treatment-related deaths occurred in Arm A. Conclusions This study suggested that the chemoradiotherapy using S-1 alone had more promising efficacy with longer-term survival, compared with induction gemcitabine followed by chemoradiotherapy for locally advanced pancreatic cancer. Clinical trial registration The study was registered at the UMIN Clinical Trials Registry as UMIN000006811.

In 2016, the American Association of Physicists in Medicine (AAPM) has published a report of task group (TG) 100 with a completely new concept, entitled "application of risk analysis methods to radiation therapy quality management." TG-100 proposed implementation of risk analysis in radiotherapy to prevent harmful radiotherapy accidents. In addition, it enables us to conduct efficient and effective quality management in not only advanced radiotherapy such as intensity-modulated radiotherapy and image-guided radiotherapy but also new technology in radiotherapy. It should be noted that treatment process in modern radiotherapy is absolutely more complex and it needs skillful staff and adequate resources. TG-100 methodology could identify weakness in radiotherapy procedure through assessment of failure modes that could occur in overall treatment processes. All staff in radiotherapy have to explore quality management in radiotherapy safety.

Aim To determine whether patients with congenital lower lid epiblepharon treated with a modified Hotz procedure combined with epicanthoplasty have a decreased recurrence rate. Patients and methods Patients with epiblepharon of the lower eyelid corrected using a modified Hotz method between 2007 and 2017 were evaluated retrospectively by chart review to determine rates of complications and recurrence as well as whether the Hotz method was combined with epicanthoplasty. The recurrence rates for patients treated with the Hotz method alone or in combination with epicanthoplasty were compared. Results A total of 60 patients (mean age, 13.6 years) and 115 eyelids were evaluated. All patients showed improvement in their symptoms and had no complications. Across the entire group, the recurrence rate for entropion was 23.5% (27 eyes). A modified Hotz procedure combined with epicanthoplasty was performed on 43 (37.4%) eyes. The recurrence rate for the group treated with a modified Hotz procedure combined with epicanthoplasty was significantly lower than that for patients who underwent the Hotz procedure alone (7.0% vs 33.3% P = 0.0012). There was no relationship between epicanthus severity and recurrence rate (P = 0.345). Conclusion In this study, we showed that patients who underwent a modified Hotz procedure combined with epicanthoplasty had a decreased recurrence rate. This improved outcome could be due to the simpler approach to the nasal side of the lower eyelid in epicanthoplasty, and epicanthoplasty can facilitate detachment of the upper eyelid from the lower eyelid.

Objectives Clinical Practice Guidelines for Pancreatic Cancer were first published in 2006 by the Japan Pancreas Society, and they were revised in 2009, 2013, and 2016. In July 2019, the Clinical Practice Guidelines for Pancreatic Cancer 2019 were newly revised in Japanese. Methods For this version, we developed the new guidelines according to the Minds Manual for Guideline Development 2017, which includes the concepts of GRADE (Grading Recommendations Assessment, Development, and Evaluation), to enable a better understanding of the current guidelines. Results The guidelines show algorithms for the diagnosis, treatment, and chemotherapy of pancreatic cancer and address 7 subjects: diagnosis, surgical therapy, adjuvant therapy, radiation therapy, chemotherapy, stent therapy, and supportive and palliative medicine. They include 56 clinical questions and 84 statements. There are statements corresponding to clinical questions, evidence levels, recommendation strengths, and agreement rates. Conclusions These guidelines represent the most standard clinical and practical management guidelines at this time in Japan. This is the English synopsis of the Clinical Practice Guidelines for Pancreatic Cancer 2019 in Japanese and is an attempt to disseminate the Japanese guidelines worldwide for introducing the Japanese approach for clinical management of pancreatic cancer.

The ongoing, Phase Ib MONALEESASIA study is evaluating the efficacy and safety of ribociclib plus endocrine therapy in Asian patients with hormone receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer. Eligible patients from Japan, Hong Kong, and Singapore were enrolled in this 2‐phase study consisting of a dose‐escalation phase to determine the maximum‐tolerated dose and the recommended Phase II dose of ribociclib plus letrozole, and a dose‐expansion phase to evaluate safety and tolerability of ribociclib plus letrozole, fulvestrant, or tamoxifen. An exploratory biomarker analysis evaluating expression of target genes was also conducted. In the dose‐escalation phase, the maximum‐tolerated/recommended Phase II doses of ribociclib were lower in Japanese patients (300 mg) than in Asian non‐Japanese patients (600 mg). Ribociclib plus endocrine therapy at the recommended Phase II dose had a manageable safety profile, with neutropenia and elevated liver transaminases being the most common adverse events leading to dose modifications or discontinuations, and it demonstrated evidence of clinical activity in both Japanese and Asian non‐Japanese patients. Preliminary efficacy in Asian populations is similar to that observed in White populations studied in previous ribociclib (MONALEESA) trials. Biomarker analysis demonstrated suppression of pharmacodynamic biomarker gene expression, indicating inhibition of target genes by ribociclib combined with endocrine therapy. Results from the ongoing study support the use of ribociclib in combination with letrozole in Asian non‐Japanese patients at the same dose (600 mg) as White patients. In Japanese patients, a lower dose of ribociclib (300 mg) should be considered. Clinicaltrials.gov: NCT02333370., The recommended Phase II dose of ribociclib, a CDK4/6 inhibitor, when given with endocrine therapy, was determined in Asian patients with HR+, HER2– advanced breast cancer. The recommended dose was established to be lower in Japanese patients, but similar in Asian non‐Japanese patients, compared with White patients. Importantly, the combination therapies presented a manageable safety profile and demonstrated evidence of clinical activity in both Asian populations, supporting the use of ribociclib in the treatment of these patients.

A phase II study of adaptive two-step intensity-modulated radiotherapy (IMRT) with chemotherapy for nasopharyngeal cancer (NPC) (JCOG1015) was conducted to evaluate the efficacy and safety. Patients aged 20–75 years with stages II–IVB NPC were enrolled. As adaptive two-step IMRT, computed tomography planning was performed twice before IMRT for the initial plan of 46 Gy/23 fractions and during treatment for the boost plan of 24 Gy/12 fractions with a total dose of 70 Gy. Chemotherapy (cisplatin 80 mg/m2/3-weeks × 3 courses) was administered concurrently with IMRT, followed by adjuvant chemotherapy (cisplatin at 70 mg/m2 with 5-FU 700 at mg/m2 for 5 days/4 weeks × 3 courses). Between 2011 and 2014, 75 patients were enrolled from 12 institutions. The 3-year overall survival (OS) for the 75 patients was 88%, and the upper and lower limits of the 95% CI of 78%–94% were higher than the expected 3-year OS of 75% for the target population adjusted by the actual proportion of stage II:III:IV = 21%:44%:35%. The 3-year progression-free survival (PFS) and loco-regional PFS were 71% [59–80%] and 77% [66–85%], respectively. Although no grade 4–5 late toxicities were observed, 15 patients (20%) developed grade 3 late toxicities. Grade 2 xerostomia was noted in 26%, 12%, and 9% at 1, 2, and 3 years after starting IMRT, respectively. Adaptive two-step IMRT for NPC demonstrated an excellent 3-year OS with acceptable toxicities. This method may be one treatment option for locally advanced NPC.

A randomized phase III trial was initiated in Japan in August 2019 to confirm the superiority of preoperative chemoradiotherapy followed by surgery plus adjuvant chemotherapy compared to the standard treatment, i.e. surgery plus adjuvant chemotherapy, for locally recurrent rectal cancer in local relapse-free survival. In all, 110 patients from 43 Japanese institutions will be recruited over a period of 6 years. Eligible patients would be registered and randomly assigned to each group with an allocation ratio of 1:1. The primary endpoint is local relapse-free survival. The secondary endpoints are overall survival, relapse-free survival, proportion of local relapse, proportion of distant relapse, proportion of patients with pathological R0 resection, response rate of preoperative chemoradiotherapy (preoperative chemoradiotherapy arm), pathological complete response rate (preoperative chemoradiotherapy arm), proportion of patients who completed the protocol treatment, incidence of adverse events (adverse reactions) and quality of life after surgery. This trial has been registered at the Japan Registry of Clinical Trial: jRCTs031190076 [https://jrct.niph.go.jp/latest-detail/jRCTs031190076] and ClinicalTrials.gov: NCT04288999 [https://clinicaltrials.gov/ct2/show/NCT04288999].

JCOG0909 is a phase II trial of definitive chemoradiotherapy including salvage treatment for cStage II–III thoracic esophageal cancer; the radiation field for elective regional lymph node irradiation, which can affect patient outcome and adverse event, varied based on the primary tumor site, i.e., upper (Ut), middle (Mt), and lower thoracic (Lt) esophagus. The impact of different primary sites on the safety and efficacy of definitive chemoradiotherapy in JCOG0909 is not well characterized. Patients were categorized into three groups (Ut, Mt, and Lt) according to the primary tumor location. We compared acute adverse events during definitive chemoradiotherapy, complete response (CR) rate, 3-year progression-free survival (PFS), and overall survival (OS) among the 3 groups. Out of the 96 patients enrolled in JCOG0909 between April 2010 and August 2014, 94 patients (16, 59, and 19 patients in the Ut, Mt, and Lt groups, respectively) were included in this exploratory analysis. The proportion of patients with cStage III was 25% in the Ut, 37% in the Mt, and 47% in the Lt group. Grade 3–4 leukopenia, neutropenia, and thrombocytopenia were more frequently observed in the Mt (66%, 54%, and 15%) and Lt groups (84%, 68%, and 16%) than in the Ut group (38%, 44%, and 0%). There was no significant between-group difference with respect to 3-year OS (73.3%, 77.9%, and 57.9%), 3-year PFS (60.0%, 59.3%, and 47.4%), or CR rate (62.5%, 62.7%, and 42.1%). In JCOG0909, the incidence of severe hematological toxicity had a trend toward higher in the Mt and Lt than the Ut esophageal cancer; however, no remarkable difference by primary sites was observed with respect to efficacy endpoints.

Radiotherapy is indicated for the treatment of esophageal cancer both with curative intent and with palliative intent. Concurrent chemoradiotherapy is the standard treatment for patients in good condition who can receive chemotherapy, based on the results of randomized trial compared chemoradiotherapy with radiotherapy alone. For locally advanced unresectable esophageal cancer, definitive chemoradiotherapy is standard therapy with potentially curative intent. And for resectable esophageal cancer, definitive chemoradiotherapy is a treatment option in an attempt to preserve the esophagus from favorable results of clinical trials. These results are supported by salvage treatment in cases of residual or recurrent disease after chemoradiotherapy. However, high mortality rate of salvage surgery and high incidence of late toxicities after chemoradiotherapy with higher radiation dose are important problems to be solved. Neoadjuvant chemoradiotherapy is the standard treatment for locally advanced esophageal cancer in Western countries, however, it is investigational in Japan. Recently, prophylactic chemoradiotherapy for patients with pT1b or pT1a involving lymphovascular invasion after endoscopic resection could be a treatment option from favorable result of a clinical trial. Combination chemotherapy of new agents and new radiotherapy techniques such as intensity-modulated radiation therapy, proton-beam therapy, and heavy-particle radiotherapy have been evaluated in clinical trials to improve the treatment results including efficacy and toxicity.

Morphological change in regions with microtexture, i.e., macrozones, in Ti-6Al-4V alloy after hot-forging in α+β phase region was analyzed using SEM/EBSD technique, and then the correlation with ultrasonic reflection was investigated. Starting material had colony-type microstructure consisting of lamellar-α with the same crystallographic orientation. Forging (cogging and upsetting) was conducted in α+β phase region to produce a cylindrical material with smaller cross section, followed by air cooling. Thus, resulting microstructure consisted of granular-α. To estimate local change in elastic modulus within the materials, we analyzed crystallographic orientations of α-phase using SEM/EBSD in terms of an inclination angle of c-axis. The regions having the nearly common crystallographic orientations of α-phase were found. Shapes of such regions with microtexture were elongated along the axial direction, which formed quasi-periodic variation of the inclination angle, i.e., elastic modulus, of α-phase along the radial direction of the forged material. Ultrasonic measurement was conducted at a frequency of 5 MHz along the radial direction and the axial direction. Relationship between the morphology of regions having microtexture and the amplitude of backscattered noises was evaluated. It was considered that the quasi-periodicity of the inclination angle correlated with the amplitude of backscattered noises in ultrasonic measurement.

238 Background: Neoadjuvant treatment is the standard care for locally advanced esophageal squamous cell cancer (ESCC). JCOG1109 (UMIN000009482) compared the doublet and triplet of chemotherapy and chemoradiotherapy as neoadjuvant treatment. Methods: Eligible patients (pts) with ESCC of clinical stage IB, II, III (excluding T4) (UICC 7th) from 44 institutions were randomized 1:1:1 to neoadjuvant CF (cisplatin 80 mg/m2 on day1 plus 5-FU 800 mg/m2 on days 1-5 Q3W/2course), DCF (docetaxel 70 mg/m2 on day 1, cisplatin 70 mg/m2 on day1, plus 5-FU 750 mg/m2 on days 1-5 Q3W/3 course), or CF-RT (cisplatin 75 mg/m2 on day 1 plus 5-FU 1000 mg/m2 on days 1-4 Q4W/2course, radiation 41.4 Gy/23 fr). Primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), %R0 resection, %objective response by neoadjuvant therapy, %pathological complete response (pCR) and safety. Differences in OS was assessed in the ITT using the stratified log-rank test. The data cutoff date for the analysis was July 20, 2021. Results: Of 601 pts 199 CF, 202 DCF, and 200 CF-RT were enrolled from December 5, 2012 to July 20, 2018, respectively. Among 601 pts, 88.2% were male, median (range) age was 65 (30-75), clinical stage III (nonT4) pts were 62.6%. Median follow-up time (range) was 4.2 years (y) (0-8.5). Median OS in CF, DCF, and CF-RT arm were 4.6 y, not reached (NR), and 6.0y, and 3-year OS was 62.6%, 72.1%, and 68.3%, respectively (stratified log-rank test: p = 0.006 for CF vs. DCF and p = 0.12 for CF vs. CF-RT). By stratified Cox regression analysis for OS, hazard ratios (HR) [95% CI] was 0.68 [0.50–0.92] for CF vs. DCF and 0.84 [0.63–1.12] for CF vs. CF-RT. Median PFS in CF, DCF, and CF-RT arm were 2.7 y, NR, and 5.3 y, and 3-year PFS was 47.7%, 61.8%, and 58.5%, respectively. R0 resection was achieved in 168 (84.4%), 173 (85.6%), and 175 (87.5%), and pCR was 4 (2.1%), 40 (19.8%), and 77 (38.5%), respectively. During neoadjuvant therapy, febrile neutropenia in CF, DCF, and CF-RT arm were 1.0%, 16.3% and 4.7%, and esophagitis (grade>3) were 1.0%, 1.0% and 8.9%, respectively. The treatment-related death was seen in 3 (1.5%), 4 (2.0%), and 2 (1.0%), in CF, DCF, and CF-RT arm, respectively. Conclusions: DCF significantly improved OS over CF as neoadjuvant therapy for locally advanced ESCC, with a manageable toxicity profile. DCF represents a new standard neoadjuvant treatment for ESCC. Clinical trial information: UMIN000009482.

ObjectiveThis study explores the views of healthcare professionals regarding care and treatment goals in irreversible terminal delirium and their effect on patients and caregivers.MethodWe conducted a qualitative interview study of healthcare professionals (palliative care physician, oncologist, psycho-oncologist, and clinical psychologist) engaged in the treatment of terminally ill cancer patients. We assessed the views of healthcare workers regarding treatment goals in terminal delirium and their effect on patients and their families.ResultOf the 21 eligible healthcare professionals, 20 agreed to participate in this study. Three of the professionals had experience with treating terminal delirium as family caregivers. We identified five important aspects of treatment goals in terminal delirium based on the views of healthcare professionals: (1) adequate management of symptoms/distress, (2) ability to communicate, (3) continuity of self, (4) provision of care and support to families, and (5) considering a balance (between symptom alleviation and maintaining communication; between symptom alleviation and family preparations for the death of patients; balance between specific treatment goals for delirium and general treatment goals).Significance of resultsAccording to the views of healthcare workers questioned in this study, goals of care and treatment in terminal delirium are multidimensional and extend beyond simply controlling patient symptoms.

Background Buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus fulvestrant in the BELLE-2 study significantly improved progression-free survival (PFS) in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Patients and methods In this phase III study, patients were randomised 1:1 to buparlisib (100 mg/day; continuously in 28-day cycles) or placebo, plus fulvestrant (500 mg on cycle 1 day 15, and day 1 of subsequent cycles). Overall survival (OS) was assessed in the overall population and patients with known PI3K pathway status (both had shown significant PFS improvements). OS by PIK3CA status in circulating tumour DNA (ctDNA) was an exploratory end-point. Results A total of 2025 patients were screened for eligibility between 7th September 2012 and 10th September 2014, and 1178 received fulvestrant (500 mg) during a run-in phase; 31 discontinued. Of 1147 patients (median age 62 years), 98% had the Eastern Cooperative Oncology Group performance status ≤1, and 59% had visceral disease. Median follow-up from randomisation to data cut-off (23rd December 2016) was 37.6 months. Median OS trended in favour of the buparlisib arm in the overall population (33.2 versus 30.4 months; P = 0.045) and among patients with known PI3K pathway status (30.9 versus 28.9 months; P = 0.144); neither outcome was statistically significant. Median OS also trended in favour of buparlisib among patients with PIK3CA-mutant ctDNA (26.0 versus 24.8 months). Grade III/IV adverse events with ≥10% difference between the buparlisib versus placebo arms were elevated alanine aminotransferase (26% versus 1%), elevated aspartate aminotransferase (18% versus 3%) and hyperglycemia (15% versus Conclusions OS results were in favour of buparlisib plus fulvestrant versus placebo plus fulvestrant; however, there is no statistical significance and more frequent grade III/IV adverse events were reported. Use of more selective PI3K inhibitors might provide the greatest clinical benefit and tolerable safety profile in this setting. Further evaluation of the predictive benefit of PIK3CA-mutant ctDNA is warranted. Trial registration number NCT01610284 .

Although peripheral blood-based parameters (PBBPs) are reported as prognostic indicators in patients with breast cancers, their utility has not been studied in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Tumor-infiltrating lymphocytes (TILs) might be a predictive factor in patients with HER2-positive ABC treated with pertuzumab and trastuzumab (PT) plus docetaxel. We aimed to evaluate whether PBBPs could have predictive value in HER2-positive ABC treated with pertuzumab and trastuzumab (PT) combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX). Data from 51 patients included in two single-arm, phase II trials were included in this retrospective-prospective study; the ERI + PT (N = 30) and Nab-PTX + PT (N = 21) combinations were registered under clinical trials number UMIN000012375 and UMIN000006838, respectively. We assessed PBBPs using prospectively collected data and investigated the association with progression-free survival (PFS); we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values for ALC, NLR, and PLR were set at 1000 or 1500 cells/μL, 2, and 250, respectively. PFS was significantly improved in patients with ALC ≥1500/μL compared to those with ALC 1000–

The overall survival of SBRT for T2N0M0 NSCLC was 67.9% at 3 years and 40.8% at 5 years with low toxicity., Purpose A dose escalation study to determine the recommended dose with stereotactic body radiation therapy (SBRT) for peripheral T2N0M0 non-small cell carcinomas (JCOG0702) was conducted. The purpose of this paper is to report the survival and the late toxicities of JCOG0702. Materials and methods The continual reassessment method was used to determine the dose level that patients should be assigned to and to estimate the maximum tolerated dose. The starting dose was 40 Gy in four fractions at D95 of PTV. Results Twenty-eight patients were enrolled. Ten patients were treated with 40 Gy at D95 of PTV, four patients with 45 Gy, eight patients with 50 Gy, one patient with 55 Gy and five patients with 60 Gy. Ten patients were alive at the last follow-up. Overall survival (OS) for all patients was 67.9% (95% CI 47.3–81.8%) at 3 years and 40.8% (95% CI 22.4–58.5%) at 5 years. No Grade 3 or higher toxicity was observed after 181 days from the beginning of the SBRT. Compared to the toxicities up to 180 days, chest wall related toxicities were more frequent after 181 days. Conclusions The 5-year OS of 40.8% indicates the possibility that SBRT for peripheral T2N0M0 non-small cell lung cancer is superior to conventional radiotherapy. The effect of the SBRT dose escalation on OS is unclear and further studies are warranted.

Objectives: Kawasaki disease (KD) is one of the most common childhood vasculitides. Some serological studies have suggested an etiological relationship between KD and human herpesvirus (HHV)-6 or HHV-7. However, primary or reactivated HHV-6 and -7 has not been fully investigated in patients with KD. Methods: Twenty-three patients with KD were prospectively enrolled in this study. Peripheral blood was collected in the acute and convalescence phases, and HHV-6 and -7 viral loads were measured by real-time PCR. Results: In the acute phase, HHV-6 and -7 DNA was detected in 7 (30%) patients each, compared to 13 (57%) and 9 (39%) patients in the convalescence phase, respectively. HHV-6 and -7 DNA loads were significantly higher in the convalescence phase than in the acute phase. Significant increases in HHV-6 and -7 DNA loads were not observed in disease control patients. Taking into account HHV-6 and -7 serostatus, reactivation of HHV-6 and -7 was observed in 7 and 9 patients, respectively. KD patients with HHV-6 reactivation showed higher C-reactive protein levels and more frequently required steroid therapies than patients without reactivation. Conclusion: HHV-6 and -7 reactivation is frequent in KD patients. HHV-6 reactivation might exacerbate the severity of KD., Published online: 05 Sep 2018

Aim To investigate the intrafraction movement of the esophagus using fiducial markers. Background Studies on intrafraction esophageal motion using the fiducial markers are scarce. Materials and methods We retrospectively analyzed patients with clinical T1N0 esophageal cancer who had received fiducial markers at our hospital between July 2007 and December 2013. Real-Time Position Management System to track the patient's respiration was used, and each patient underwent three-dimensional computed tomography of the resting expiratory and inspiratory level. We used the center of the marker to calculate the distance between the expiratory and inspiratory breath-holds, which were measured with the radiotherapy treatment planning system in three directions: left–right (LR), superior–inferior (SI), and anterior–posterior (AP). The movements at each site were compared with the Kruskal–Wallis analysis and Wilcoxon rank sum test with a Bonferroni correction. Results A total of 101 patients with 201 fiducial markers were included. The upper, middle and lower thoracic positions had 40, 77, and 84 markers, respectively. The mean absolute magnitudes of the shifts (standard deviation) were 0.18 (0.19) cm, 0.68 (0.46) cm, and 0.24 (0.24) cm in the LR, SI, and AP directions, respectively. From the cumulative frequency distribution, we assumed that 0.35 cm LR, 0.8 cm SI, and 0.3 cm AP in the upper; 0.5 cm LR, 1.55 cm SI, and 0.55 cm AP in the middle; and 0.75 cm LR, 1.9 cm SI, and 0.95 cm AP in the lower thoracic esophagus covered 95% of the cases. Conclusions The internal margin based on the site of esophagus was estimated.

Earlier studies suggest progression-free survival (PFS) may be used as a surrogate endpoint for overall survival (OS) in metastatic breast cancer, which could shorten follow-up duration and speed up assessment of treatment effects. However, to our knowledge, the association between them is still unclear in advanced or metastatic triple-negative breast cancer (TNBC).A literature-based meta-analysis followed by correlation analysis was conducted in advanced or metastatic TNBC. Weighted multiple regression analysis was then used to test the strength of the association between medians of PFS and OS, and the association between HRFourteen randomized clinical trials published between January 2007 and August 2019, 31 median pairs for PFS and OS, and 17 pairs for HROur analysis suggests PFS can be strongly correlated with OS and considered a valid surrogate endpoint for OS in advanced or metastatic TNBC.

Background/aim Severe benign cicatricial stricture (SBCS) is a major complication after definitive chemoradiation therapy (dCRT) for esophageal squamous cell carcinoma (ESCC). This study was conducted to investigate risk factors of SBCS in patients with localized ESCC. Patients and methods This study included 197 patients with clinical stage (cSt) II/III ESCC with T3 primary tumor, treated with dCRT between 2000 and 2011. SBCS was defined as the inability to pass a 9-mm diameter endoscope or the presence of symptoms requiring treatment. Results Complete response was obtained in 87 patients (44%). Multivariate analysis revealed that hypoalbuminemia (hazard ratio=5.65; 95% confidence interval=1.50-21.28; p=0.010) and the inability to pass an endoscope (hazard ratio=5.90; 95% confidence interval=1.52-22.85; p=0.010) were risk factors of SBCS. Conclusion The inability to pass an endoscope and hypoalbuminemia were identified as risk factors of SBCS in patients with cSt II/III ESCC with T3 primary tumor.