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Background: Financial toxicity (FT) is a notable concern for patients with breast cancer worldwide. The situation regarding FT in Japan, however, has not been well explored. This study examined FT in patients with breast cancer in Japan and presented an overview of the group study's overall findings., Methods: The survey used the Questant application and primarily targeted patients with breast cancer attending research facilities and physicians who are members of the Japanese Breast Cancer Society. The Japanese version of the Comprehensive Score for FT (COST) was used to quantify patients' FT. Multiple regression analysis was used to identify factors related to FT in patients with breast cancer in Japan and evaluate the sufficiency of information support level (ISL) for medical expenses., Results: We collected 1558 responses from patients and 825 from physicians. In terms of factors affecting FT, recent payments had the highest impact, followed by stage, and related departments positively affecting FT. Conversely, factors such as income, age, and family support were found to negatively affect FT. A significant discrepancy was identified between patients and physicians in perceived information support, with patients frequently feeling unsupported and physicians believing that they have provided adequate support. Furthermore, differences in the frequency of explanations and opportunities to ask questions about medical costs across FT grades were found. The analysis also showed that physicians with a better understanding of information support needs and greater knowledge of medical costs tended to provide more support that is comprehensive., Conclusion: This study emphasizes the importance of addressing FT in patients with breast cancer in Japan and highlights the need for enhanced information support, deeper understanding by physicians, and collaborative efforts among professionals to mitigate financial burden and provide personalized, tailored support for individual needs., (© 2023. The Author(s).)

Surgical site infections (SSIs) after thyroid surgery are rare complications, with incidence rates of 0.3%-1.6%. Using a Japanese database, we conducted exploratory analyses on the incidence of SSIs, investigated the incidence of SSIs by the National Nosocomial Infections Surveillance risk index, and identified the causative bacteria of SSIs. SSIs occurred in 50 (0.7%) of 7388 thyroid surgery cases. Risk index-0 patients had the lowest incidence rate of SSIs (0.41%). The incidence of SSIs in risk index-1 patients was 3.05 times the incidence of SSIs in risk index-0 patients. The rate of SSI occurrence for risk index-2 patients was 4.22 times the rate of SSI occurrence for risk index-0 patients. Thirty-one bacterial species were identified as the cause of SSIs in thyroid surgery cases, of which 12 (38.7%) SSIs were caused by Staphylococcus aureus and Staphylococcus epidermidis. Of the nine SSIs caused by Staphylococcus aureus, 55.6% (five cases) were attributed to methicillin-resistant Staphylococcus aureus. Therefore, routine prophylactic antibiotic administration should be avoided, while the target for administration should be narrowed, according to the SSI risk. Administration of prophylactic antibiotics, such as 2 g piperacillin or 1 g cefazolin, is considered appropriate., (© 2022 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Background: Cancer patients experience various forms of psychological distress. Their distress, mainly in the form of depression and anxiety, leads to poor quality of life, increased medical spending due to frequent visits, and decrease in treatment adherence. It is estimated that 30-50% among them would require support from mental health professionals: in reality, much less actually receive such support partly due to a shortage of qualified professionals and also due to psychological barriers in seeking such help. The purpose of the present study is to develop the easily accessible and the most efficient and effective smartphone psychotherapy package to alleviate depression and anxiety in cancer patients., Methods: Based on the multiphase optimization strategy (MOST) framework, the SMartphone Intervention to LEssen depression/Anxiety and GAIN resilience project (SMILE-AGAIN project) is a parallel-group, multicenter, open, stratified block randomized, fully factorial trial with four experimental components: psychosocial education (PE), behavioral activation (BA), assertion training (AT), and problem-solving therapy (PS). The allocation sequences are maintained centrally. All participants receive PE and then are randomized to the presence/absence of the remaining three components. The primary outcome of this study is the Patient Health Questionnaire-9 (PHQ-9) total score, which will be administered as an electronic patient-reported outcome on the patients' smartphones after 8 weeks. The protocol was approved by the Institutional Review Board of Nagoya City University on July 15, 2020 (ID: 46-20-0005). The randomized trial, which commenced in March 2021, is currently enrolling participants. The estimated end date for this study is March 2023., Discussion: The highly efficient experimental design will allow for the identification of the most effective components and the most efficient combinations among the four components of the smartphone psychotherapy package for cancer patients. Given that many cancer patients face significant psychological hurdles in seeing mental health professionals, easily accessible therapeutic interventions without hospital visits may offer benefits. If an effective combination of psychotherapy is determined in this study, it can be provided using smartphones to patients who cannot easily access hospitals or clinics., Trial Registration: UMIN000041536, CTR. Registered on 1 November 2020  https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000047301 ., (© 2023. The Author(s).)

Assessments of patient-reported outcomes and health-related quality of life in cancer clinical trials have been increasingly emphasized recently because patient and public involvement in cancer treatment development has been promoted by regulatory authorities and academic societies. To assess patient experiences during and after cancer treatment, there is interest in implementing patient-reported outcome and health-related quality of life assessments into cancer clinical trials. The Japan Clinical Oncology Group quality of life ad hoc committee previously created a version of the Quality of Life Assessment Policy in 2006. Recently, there has been increasing demand from Japan Clinical Oncology Group researchers to assess patient-reported outcome/health-related quality of life in clinical trials. Although guidelines are available regarding planning and reporting clinical trials that include patient-reported outcome/health-related quality of life as an endpoint, there are still issues regarding the lack of consensus on standardized methods for analysing and interpreting the results. Hence, it was considered necessary to reorganize the Japan Clinical Oncology Group patient-reported outcome/quality of life research committee and to revise the former patient-reported outcome/quality of life research policy to promote patient-reported outcome/health-related quality of life research in future Japan Clinical Oncology Group trials. The purpose of this Japan Clinical Oncology Group patient-reported outcome/quality of life research policy is to define patient-reported outcome/health-related quality of life research and provide guidelines for including patient-reported outcome/health-related quality of life as an endpoint in Japan Clinical Oncology Group trials., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background/aim: Currently, several ongoing prospective studies are investigating the safety of breast surgery omission in patients with breast cancer who are exceptional responders to neoadjuvant chemotherapy. However, there is little information about the preferences of these patients regarding omission of breast surgery., Patients and Methods: We conducted a questionnaire survey to assess preferences regarding omission of breast surgery among patients with breast cancer who had human epidermal growth factor receptor 2-positive or estrogen receptor-negative tumors and good clinical response after neoadjuvant chemotherapy. Patients' estimation of the risk of ipsilateral breast tumor recurrence (IBTR) after definitive surgery or breast surgery omission was also assessed., Results: Of 93 patients, only 22 (23.7%) said they would omit breast surgery. Under the scenario of omitting breast surgery, the 5-year IBTR rate estimated by patients who said they would omit breast surgery was significantly lower (median, 10%) than the rate estimated by patients who preferred undergoing definitive surgery (median, 30%) (p=0.017)., Conclusion: The proportion of our surveyed patients who were willing to omit breast surgery was low. Patients who said they preferred to omit breast surgery overestimated the 5-year IBTR risk., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The area of residual tumor (ART) is a prognostic factor in patients treated with neoadjuvant chemotherapy (NAC) for lung, pancreatic, and rectal cancers. This study aimed to evaluate the usefulness of ART as a method for predicting the prognosis of triple-negative breast cancer (TNBC) patients after NAC. We included 143 patients with TNBC treated with NAC. The ART at the maximum cut surface of the residual tumor was measured. We divided the patients into three groups: ART-0 (ART = 0 mm 2 ), ART-low (0 mm 2  < ART ≤ 136mm 2 ), and ART-high (ART > 136 mm 2 ), and compared their clinicopathologic factors and prognosis. There were no significant differences in either recurrence-free survival (RFS) or overall survival (OS) between ART-0 and ART-low; however, the ART-high group had significantly shorter RFS and OS than the ART-0 and ART-low groups. Multivariate analysis showed that ART-0 and -low and ypN(-) were independent favorable prognostic factors for RFS. Groups with both ART-low and ypN(-) as well as those with ART-0 and ypN(-) showed significantly longer OS and RFS than the other groups (P < .05). Moreover, there was no significant difference in the RFS and OS between the ART-0 and ypN(-) groups and the ART-low and ypN(-) groups (P = .249 and P = .554, respectively). We concluded that ART is a candidate histopathological evaluation method for predicting the prognosis of TNBC patients treated with NAC. Furthermore, postoperative chemotherapy could be omitted in patients with ART-0 and ypN(-) (pathological complete response) and those with ART-low and ypN(-)., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Although there is a lack of data on health-state utility values (HSUVs) for calculating quality-adjusted life-years in Japan, cost-utility analysis has been introduced by the Japanese government to inform decision making in the medical field since 2016., Objectives: This study aimed to determine whether the Lloyd model which was a predictive model of HSUVs for metastatic breast cancer (MBC) patients in the UK can accurately predict actual HSUVs for Japanese patients with MBC., Design: The prospective observational study followed by the validation study of the clinical predictive model., Setting and Participants: Forty-four Japanese patients with MBC were studied at 336 survey points., Methods: This study consisted of two phases. In the first phase, we constructed a database of clinical data prospectively and HSUVs for Japanese patients with MBC to evaluate the predictive accuracy of HSUVs calculated using the Lloyd model. In the second phase, Bland-Altman analysis was used to determine how accurately predicted HSUVs (based on the Lloyd model) correlated with actual HSUVs obtained using the EuroQol 5-Dimension 5-Level questionnaire, a preference-based measure of HSUVs in patients with MBC., Results: In the Bland-Altman analysis, the mean difference between HSUVs estimated by the Lloyd model and actual HSUVs, or systematic error, was -0.106. The precision was 0.165. The 95% limits of agreement ranged from -0.436 to 0.225. The t value was 4.6972, which was greater than the t value with 2 degrees of freedom at the 5% significance level (p=0.425)., Conclusions: There were acceptable degrees of fixed and proportional errors associated with the prediction of HSUVs based on the Lloyd model for Japanese patients with MBC. We recommend that sensitivity analysis be performed when conducting cost-effectiveness analyses with HSUVs calculated using the Lloyd model., Competing Interests: Competing interests: KT received honoraria from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eizai, Eli Lilly Japan KK, Nippon Kayaku, Pfizer, Taiho Pharmaceutical and Takeda Pharmaceutical., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We aimed to determine the dynamic trends in health state utility values (HSUVs) in patients with end-stage breast cancer. We selected 181 patients comprising 137 with primary breast cancer (PBC) and 44 with metastatic breast cancer (MBC) (28 survivors and 16 patients with MBC death). HSUVs were 0.90 and 0.89 in patients with PBC and 0.83 and 0.80 in those with MBC (survivors) at 6 and 3 months, respectively, before the end of the observation period; these values were 0.73 and 0.66, respectively, in those with MBC (deceased) during the aforementioned period. The root-mean-squared error (RMSE) for the decrease in HSUVs over 3 months was 0.10, 0.096, and 0.175 for patients with PBC, MBC (survivors), and MBC (deceased), respectively. One-way analysis of variance for differences in absolute error among the groups was significant ( p = 0.0102). Multiple comparisons indicated a difference of 0.068 in absolute error between patients with PBC and those with MBC (deceased) ( p = 0.0082). Patients with end-stage breast cancer had well-controlled HSUVs 3 months before death, with a sharp decline in HSUVs in the 3 months leading up to death.

Coenzyme A (CoA) is an essential cofactor present in all domains of life and is involved in numerous metabolic pathways, including fatty acid metabolism, pyruvate oxidation through the tricarboxylic acid (TCA) cycle, and the production of secondary metabolites. This characteristic makes CoA a commercially valuable compound in the pharmaceutical, cosmetic, and clinical industries. However, CoA is difficult to accumulate in living cells at a high level, since it is consumed in multiple metabolic pathways, hampering its manufacturing by typical cell cultivation and extraction approaches. The feedback inhibition by CoA to a biosynthetic enzyme, pantothenate kinase (PanK), is also a serious obstacle for the high-titer production of CoA. To overcome this challenge, in vitro production of CoA, in which the CoA biosynthetic pathway was reconstructed outside cells using recombinant thermophilic enzymes, was performed. The in vitro pathway was designed to be insensitive to the feedback inhibition of CoA using CoA-insensitive type III PanK from the thermophilic bacterium Thermus thermophilus. Furthermore, a statistical approach using design of experiments (DOE) was employed to rationally determine the enzyme loading ratio to maximize the CoA production rate. Consequently, 0.94 mM CoA could be produced from 2 mM d-pantetheine through the designed pathway. We hypothesized that the insufficient conversion yield is attributed to the high K m value of T. thermophilus PanK toward ATP. Based on these observations, possible CoA regulation mechanisms in T. thermophilus and approaches to improve the feasibility of CoA production through the in vitro pathway have been investigated. IMPORTANCE The biosynthesis of coenzyme A (CoA) in bacteria and eukaryotes is regulated by feedback inhibition targeting type I and type II pantothenate kinase (PanK). Type III PanK is found only in bacteria and is generally insensitive to CoA. Previously, type III PanK from the hyperthermophilic bacterium Thermotoga maritima was shown to defy this typical characteristic and instead shows inhibition toward CoA. In the present study, phylogenetic analysis combined with functional analysis of type III PanK from thermophiles revealed that the CoA-sensitive behavior of type III PanK from T. maritima is uncommon. We cloned type III PanKs from Thermus thermophilus and Geobacillus sp. strain 30 and showed that neither enzyme's activities were inhibited by CoA. Furthermore, we utilized type III PanK for a one-pot cascade reaction to produce CoA.

In a substantial number of patients, ductal carcinoma in situ (DCIS) of the breast will never progress to invasive ductal carcinoma, and these patients are often overtreated under the current clinical criteria. Although various candidate markers are available, relevant markers for delineating risk categories have not yet been established. In this study, we analyzed the clinical characteristics of 431 patients with DCIS and performed whole-exome sequencing analysis in a 21-patient discovery cohort and targeted deep sequencing analysis in a 72-patient validation cohort. We determined that age <45 years, HER2 amplification, and GATA3 mutation are possible indicators of relapse. PIK3CA mutation negativity and PgR negativity were also suggested to be risk factors. Spatial transcriptome analysis further revealed that GATA3 dysfunction upregulates epithelial-to-mesenchymal transition and angiogenesis, followed by PgR downregulation. These results reveal the existence of heterogeneous cell populations in DCIS and provide predictive markers for classifying DCIS and optimizing treatment.

Background: Advance care planning (ACP) is a process that supports adults in understanding and sharing their personal values, life goals, and preferences regarding future medical care. We examined the current status of ACP and end-of-life (EOL) communication between oncologists and patients with metastatic breast cancer., Materials and Methods: We conducted a survey among 41 institutions that specialize in oncology by using an online tool in October 2019. Participants (118 physicians) from 38 institutions completed a 39-item questionnaire that measured facility type and function; physicians' background and clinical approach, education about EOL communication, and understanding about ACP; and the current situation of ACP and EOL discussions., Results: Ninety-eight responses concerning physicians' engagement in ACP with patients were obtained. Seventy-one (72%) answered that they had engaged in ACP. Among these, 23 (33%) physicians used a structured format to facilitate the conversation in their institutions, and only 6 (8%) settled triggers or sentinel events for the initiation of ACP. In the multivariable analysis, only the opportunity to learn communication skills was associated with physicians' engagement with ACP (odds ratio: 2.8, 95% confidence interval: 1.1-7.0). The frequency and timing of communication about ACP and EOL care with patients substantially varied among the oncologists. Communication about patients' life expectancy was less frequent compared with other topics., Conclusion: The opportunity to improve EOL communication skills promoted physicians' engagement with ACP among patients with metastatic/advanced breast cancer. However, there were still substantial variabilities in the method, frequency, and timing of ACP and EOL communication among the oncologists., Implications for Practice: This study found that the opportunity to improve end-of-life (EOL) communication skills promoted physicians' engagement in advance care planning (ACP) among patients with metastatic/advanced breast cancer. All oncologists who treat said patients are encouraged to participate in effective education programs concerning EOL communication skills. In clinical practice, there are substantial variabilities in the method, frequency, and timing of ACP and EOL communication among oncologists. As recommended in several clinical guidelines, the authors suggest a system that identifies patients who require conversations about their care goals, a structured format to facilitate the conversations, and continuous measurement for improving EOL care and treatment., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

In April 2016, the Japanese government introduced health technology assessment as a response to rising medical expenses due to 'medical innovation'. This study investigates how Japanese breast cancer patients who received treatment in Japan consider the financial value (willingness-to-pay; WTP) for their life and health by using the contingent valuation method (CVM) prospectively. First, 168 patients (84 primary breast cancer patients and 84 metastatic breast cancer patients) were pre-examined their WTP with dichotomous-choice method survey form. Next, 1,596 patients (798 primary breast cancer patients and 798 metastatic breast cancer patients) will be surveyed to their WTP for hypothetical scenarios in CVM. Based on our results, we will construct an evaluation axis from the patients' viewpoint for the cost-effectiveness of clinical trials to establish standard treatments for breast cancer. We believe this research can contribute to create a meaningful healthcare system for patients, clinicians, industries, and healthcare policymakers., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background/aims: Monensin, an Na ionophore, increases intracellular Na ([Na]i). Alteration of [Na]i influences ion transport through the sarcolemmal membrane. So far, the effects of monensin on ventricular myocytes have not been examined in detail. The main objective of this study was to elucidate the mechanism via which monensin-evoked increases in [Na]i affect the membrane potential and currents in ventricular myocytes of guinea pigs., Methods: Membrane potentials and currents were measured using the whole-cell patch-clamp technique in single myocytes. The concentration of intracellular Ca ([Ca]i) was evaluated by measuring fluorescence intensity of Fluo-4., Results: Monensin (10-5M) shortened the action potential duration (APD) and reduced the amplitude of the plateau phase. In addition, monensin decreased the sodium current (INa) and shifted the inactivation curve to the hyperpolarized direction. Moreover, it decreased the L-type calcium current (ICa). However, this effect was attenuated by increasing the buffering capacity of [Ca]i. The Na-Ca exchange current (INa-Ca) was activated particularly in the reverse mode. Na-K pump current (INa-K) was also activated. Notably, the inward rectifying K current (IK1) was not affected, and the change in the delayed outward K current (IK) was not evident., Conclusion: These results suggest that the monensin-induced shortened APD and reduced amplitude of the plateau phase are primarily due to the decrease in the ICa, the activation of the reverse mode of INa-Ca, and the increased INa-K, and second due to the decreased INa. The IK and the IK1 may not be associated with the abovementioned changes induced by monensin. The elevation of [Na]i can exert multiple influences on electrophysiological phenomena in cardiac myocytes., (© 2020 S. Karger AG, Basel.)

An amendment to this paper has been published and can be accessed via the original article.

Background: Trastuzumab (Tmab), pertuzumab (Pmab), and taxane has been a standard first-line treatment for recurrent or metastatic human epidermal growth factor (HER2)-positive breast cancer (HER2 + mBC) but has some safety issues due to taxane-induced toxicities. This has led to ongoing efforts to seek less toxic alternatives to taxanes that are equally effective when used in combination with Tmab plus Pmab. This study aims to show the non-inferiority of eribulin, a non-taxane microtubule inhibitor, against taxane, as a partner for dual HER2 blockade., Methods/design: This multicenter, randomized, open-label, parallel-group, phase III study will involve a total of 480 Japanese women with HER2 + mBC who meet the following requirements: (1) age 20-70 years; (2) no prior cytotoxic chemotherapy (excluding trastuzumab-emtansine) for mBC; (3) ≥ 6 months after prior neoadjuvant or adjuvant cytotoxic chemotherapy; (4) presence of any radiologically evaluable lesion; (5) left ventricular ejection fraction ≥ 50%; (6) Eastern Cooperative Oncology Group performance status score of 0 or 1; (7) adequate organ function; and (8) life expectancy of at least 6 months. They will be randomized 1:1 to receive eribulin (1.4 mg/m 2 on days 1 and 8) or taxane (docetaxel 75 mg/m 2 on day 1 or paclitaxel 80 mg/m 2 on days 1, 8, and 15) in combination with Tmab (8 mg/kg then 6 mg/kg) plus Pmab (840 mg then 420 mg) on day 1 of each 21-day cycle. The treatment will be continued until disease progression or unmanageable toxicity. The primary endpoint is progression-free survival as per investigator according to RECIST v1.1 criteria. Key secondary endpoints include objective response rate, overall survival, quality of life and safety. Non-inferiority will be tested with two margins of 1.33 and 1.25 in a stepwise manner. If non-inferiority is shown with a margin of 1.25, superiority will then be tested., Discussion: If this study shows the non-inferiority, or even superiority, of Tmab, Pmab, and eribulin against the existing taxane-containing regimen, this new regimen may become a standard first- or second-line treatment option for HER2 + mBC in Japan., Trial Registration: ClinicalTrials.gov, ID: NCT03264547. Registered on 28 June 2017.

Background: In treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, the efficacy of capecitabine combined with HER2-directed agents such as trastuzumab and lapatinib is supported by some evidence. The combination of T-DM1 and S-1, another oral 5-FU, may be a safe alternative treatment for metastatic breast cancer., Objectives: The optimal dose of S-1 was evaluated in combination with T-DM1 for patients with HER2-positive advanced or metastatic breast cancer. The safety and clinical response of this combination treatment were also assessed., Methods: This 3 + 3 dose-escalation study of S-1 given for the first 2 of 3 weeks, in combination with T-DM1 (3.6 mg/kg given every 3 weeks) to patients with trastuzumab-pretreated HER2-positive advanced or metastatic breast cancer was designed to evaluate the dose-limiting toxicity (DLT) occurrence in the first cycle. We also evaluated the safety and clinical activity of this combination treatment in multiple cycles. Two different dose levels of S-1 (65 and 80 mg/m2/day) were planned, although the capecitabine arm was abandoned because of slow recruitment., Results: Twelve out of the 13 patients enrolled were evaluable for DLT. One DLT (grade ≥3 non-hematological adverse events) occurred at dose level 0, leading to the expansion of this cohort to 6 patients, with an additional DLT (≥7 days discontinuation of medication), while no DLT occurred at dose level 1. As a result, the maximum tolerable dose of S-1 was determined to be 80 mg/m2/day for 14 days with T-DM1 3.6 mg/kg, repeated every 3 weeks. Two patients had grade 3 thrombocytopenia at dose level 0, and 1 patient at dose level 1., Conclusions: S-1 can be safely combined with the clinically relevant dose of T-DM1 in patients with HER2-positive advanced or metastatic breast cancer. Further evaluation with a larger sample size is required for efficacy assessment., (© 2019 S. Karger AG, Basel.)

The double-stranded RNA-binding protein TARBP2 has been suggested to act as an upstream regulator of breast cancer metastasis by destabilizing transcripts of the possible metastasis suppressors amyloid precursor protein (APP) and ZNF395. We examined this hypothesis by immunostaining of TARBP2, APP, and ZNF395 in 200 breast cancer specimens using tissue microarrays and analyzed the relationships between expression levels and clinicopathological parameters and prognosis. Increased TARBP2 overexpression was associated with shorter overall survival and disease-free survival, and increased but not reduced APP expression correlated with lower overall survival and disease-free survival. ZNF395 expression levels had no prognostic value, but reduced expression correlated with reduced lymph node metastasis. There was no significant relationship between TARBP2 overexpression and reduced APP and/or ZNF395 expression. Patients with tumors with higher TARBP2 or APP expression had unfavorable prognoses. Although reduced ZNF395 expression was significantly related to reduced lymph node metastasis, further studies are needed to clarify the role of TARBP2/APP/ZNF395 in breast cancer., Competing Interests: Authors disclose no potential conflicts of interest.

Background: Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, and more than 880,000 people are estimated to be infected with HCV in Japan. Little information is available on the outcomes of HCV during chemotherapy for solid tumors, and the impact of HCV infection on toxicity of chemotherapy is unknown., Materials and Methods: We performed a retrospective survey of 1,110 patients diagnosed with breast cancer between January 2006 and March 2011 at our institution. All patients had been screened for hepatitis C serology at diagnosis of breast cancer. We retrospectively investigated the change in HCV load and the toxicities of chemotherapy, based on review of their medical records., Results: 23 patients were identified as having a positive test for anti-HCV antibodies. Ten of these patients received chemotherapy. Their median age was 66 years. No patient had decompensated liver disease at baseline. Eight patients received cytotoxic agents with or without trastuzumab, and two patients received trastuzumab alone. Four of eight patients who received cytotoxic chemotherapy developed febrile neutropenia and one developed transaminases elevation. Serum HCV-ribonucleic acid (RNA) level before and after chemotherapy was evaluated in six patients. Median serum HCV-RNA level at baseline and after chemotherapy was 6.5 and 6.7 logIU/ml, respectively., Conclusion: Chemotherapy for breast cancer patients with HCV infection is feasible, and viral load doesn't change during the chemotherapy.

Objective: The aims of the present study were as follows: (i) to clarify the proportion of women who experience psychological distress during breast cancer diagnosis and (ii) to identify the predictors of psychological distress related to the diagnostic process., Methods: This was a longitudinal prospective study of women who required further breast examination. Questionnaires were administered at pre-medical consultations (Time 1), after describing radiological examination (Time 2), and after explaining pathological findings (Time 3). All participants completed Hospital Anxiety and Depression Scale (HADS), Functional Assessment of Cancer Therapy--Breast, and Functional Assessment of Chronic Illness Therapy--Spiritual subscale at Time 1 to identify predictors. Participants also completed HADS at Times 2 and 3 to identify the presence or absence of psychological distress., Results: Of the 222 eligible patients, at Time 2, 31 (22.6%) participants with no clinical abnormalities and 39 (45.9%) participants with abnormal findings had HADS scores of ≥ 11 points (χ2 test, 13.14; p < 0.001). At Time 3, 14 (28.0%) participants with benign breast changes and 24 (68.6%) participants with breast cancer had scores of ≥ 11 (χ2 test, 13.71; p < 0.001). Higher HADS scores at Time 1 were associated with the presence of psychological distress at all stages of breast cancer diagnosis. Advanced tumor stage was a predictor of psychological distress for participants with breast cancer (odds ratios = 3.314, 95% confidence interval = 1.033-9.509; p = 0.044)., Conclusion: These results suggest that intensive psychological intervention is necessary for breast cancer patients with large tumors, as well as for women with suspected breast cancer with high HADS scores at pre-consultation., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: This retrospective study aimed to determine whether adverse events are more common in docetaxel followed by cyclophosphamide (TC) as compared to the reverse infusion order (rTC)., Methods: A retrospective analysis was undertaken at a single institution for 92 consecutive cases treated with TC or rTC for stage I-III breast cancer in a neoadjuvant/adjuvant setting between December 2006 and June 2011. TC was administered during the first 2.5 years and rTC in the latter 2 years., Results: Among the 92 cases, 50 were in the TC arm and 42 in the rTC arm. Fatigue (72.0 vs. 23.8%), edema (48.0 vs. 16.7%), peripheral neuropathy (66.0 vs. 14.3%), myalgia (48.0 vs. 9.5%) and stomatitis (48.0 vs. 16.7%) occurred significantly more often in cases receiving TC compared to rTC, respectively., Conclusion: Nonhematological toxicities are less common in cases receiving rTC in comparison to those receiving TC., (Copyright © 2013 S. Karger AG, Basel.)

Objective: Multiple endocrine neoplasia type 1 (MEN1) is less well recognized in Asian countries, including Japan, than in the West. The clinical features and optimal management of MEN1 have yet to be clarified in Japan. The aim of this study was to clarify the clinical features of Japanese patients with MEN1., Design/patients: We established a MEN study group designated the 'MEN Consortium of Japan' in 2008, and asked physicians and surgeons to provide clinical and genetic information on patients they had treated. Of 680 registered patients, 560 were analysed., Measurements: Clinical and genetic features of Japanese patients with MEN1 were examined., Results: Primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumours (GEPNET), and pituitary tumours were seen in 94·4%, 58·6% and 49·6% of patients, respectively. The prevalence of insulinoma was higher in the Japanese than in the West (22%vs 10%). In addition, 37% of patients with thymic carcinoids were women, while most were men in western countries. The MEN1 mutation positive rate was 91·7% in familial cases and only 49·3% in sporadic cases. Eight novel mutations were identified. Despite the availability of genetic testing for MEN1, the application of genetic testing, especially presymptomatic diagnosis for at-risk family members appeared to be insufficient., Conclusions: We established the first extensive database for Asian patients with MEN1. Although the clinical features of Japanese patients were similar to those in western countries, there were several characteristic differences between them., (© 2012 Blackwell Publishing Ltd.)

Nodular fasciitis of the breast is a rare, benign, soft-tissue tumor that can clinically and radiologically mimic invasive ductal carcinoma. A 25-year-old woman presented with a palpable lesion in the lower inner aspect of the left breast. Radiologically, breast carcinoma could not be excluded. On examination of the core needle biopsy, the tumor was characterized histologically as a spindle cell tumor. Excisional biopsy was performed. The tumor was diagnosed as nodular fasciitis of the breast. The imaging and histological findings of this case are presented.

The US oncology 9735 study showed the superior result of TC (docetaxel/cyclophosphamide) over AC (doxorubicin/cyclophosphamide), and now TC has been widely adopted for the treatment of early breast cancer. But in Japan there are few data on the safety and tolerability of this regimen. From January 2007 to April 2009, we treated 51 early breast cancer patients with TC in our hospital, and we summarized safety and tolerability profile, including hematologic toxicity and nonhematologic toxicity. Our patients experienced more febrile neutropenia (25.5%) compared with the original USO 9735 result (5%). This might be because we did not use prophylactic oral antibiotics. Skin toxicity was sometimes troublesome, including 3 cases (5.9%) of grade 3 skin rash. Toxicity assessment showed more asthenia, edema, neuropathy and myalgia, as is well known. Finally, we recommend prophylactic oral antibiotics, steroid premedication from the day before treatment and skin moisture, which may minimize the toxicity.

Heparan sulfate is a ubiquitous glycosaminoglycan in the extracellular matrix of most animals. It interacts with various molecules and exhibits important biological functions. K5 antigen produced by Escherichia coli strain K5 is a linear polysaccharide N-acetylheparosan consisting of GlcUA beta1-4 and GlcNAc alpha1-4 repeating disaccharide, which forms the backbone of heparan sulfate. Region 2, located in the center of the K5-specific gene cluster, encodes four proteins, KfiA, KfiB, KfiC, and KfiD, for the biosynthesis of the K5 polysaccharide. Here, we expressed and purified the recombinant KfiA and KfiC proteins and then characterized these enzymes. Whereas the recombinant KfiC alone exhibited no GlcUA transferase activity, it did exhibit GlcUA transferase and polymerization activities in the presence of KfiA. In contrast, KfiA had GlcNAc transferase activity itself, which was unaffected by the presence of KfiC. The GlcNAc and GlcUA transferase activities were analyzed with various truncated and point mutants of KfiA and KfiC. The point mutants replacing aspartic acid of a DXD motif and lysine and glutamic acid of an ionic amino acid cluster, and the truncated mutants deleting the C-terminal and N-terminal sites, revealed the essential regions for GlcNAc and GlcUA transferase activity of KfiC and KfiA, respectively. The interaction of KfiC with KfiA is necessary for the GlcUA transferase activity of KfiC but not for the enzyme activity of KfiA. Together, these results indicate that the complex of KfiA and KfiC has polymerase activity to synthesize N-acetylheparosan, providing a useful tool toward bioengineering of defined heparan sulfate chains.

Alpha/beta-galactoside alpha2,3-sialyltransferase produced by Photobacterium phosphoreum JT-ISH-467 is a unique enzyme that catalyzes the transfer of N-acetylneuraminic acid residue from cytidine monophosphate N-acetylneuraminic acid to acceptor carbohydrate groups. The enzyme recognizes both mono- and di-saccharides as acceptor substrates, and can transfer Neu5Ac to both alpha-galactoside and beta-galactoside, efficiently. To elucidate the structural basis for the broad acceptor substrate specificity, we determined the crystal structure of the alpha2,3-sialyltransferase in complex with CMP. The overall structure belongs to the glycosyltransferase-B structural group. We could model a reasonable active conformation structure based on the crystal structure. The predicted structure suggested that the broad substrate specificity could be attributed to the wider entrance of the acceptor substrate binding site.

Gag-specific CTLs are known to have stronger ability to control HIV-1 replication than others that are protein-specific. Therefore, the analysis of Gag escape mutants is expected to clarify the mechanisms of immune control in HIV-1-infected donors. However, only a limited number of Gag escape mutants have been identified so far. A previous study suggested the possibility that Gag28-3R (KW9-3R) is an escape mutant from HLA-A*2402-restricted KW9-specific CTLs but did not show any evidence of it. Here we sought to demonstrate that KW9-3R is selected as escape mutant by KW9-specific CTLs. KW9-specific CTLs showed a remarkable reduction in recognition of target cells infected with the KW9-3R mutant. The sequence analysis of HIV-1 from 58 HIV-1-infected individuals showed that the frequency of the KW9-3R mutant was significantly higher in HLA-A*2402(+) individuals than in HLA-A*2402(-) individuals. Longitudinal analysis of an HLA-A*2402(+) individual with HIV-1 early infection showed that this escape mutant was selected over an approximately 2-year period. These results together indicate that Gag28-3R is an escape mutant selected by HLA-A*2402-restricted KW9-specific CTLs. Further analysis of this epitope will clarify the role of HIV-1-specific CTLs in the control of HIV-1 among the Japanese population, since 70% of them carry this allele.

Adenomatous polyposis coli (APC), whose mutation causes colorectal cancers, is a key player in the Wnt signaling pathway. While the role of APC in inhibition of beta-catenin/LEF1-dependent activation of transformation-inducing genes has been intensively studied and well established, regulation of APC expression at the protein level is only partially understood. Here we report that APC is up-regulated by EDD, the mammalian orthologue of Drosophila melanogaster"hyperplastic discs" gene (hyd) that is considered to be a putative tumor suppressor. Screening of APC immunocomplexes by mass spectrometry identified EDD as a putative APC-interacting protein. Exogenously expressed and endogenous APC interacted with EDD in vivo. Indirect immunofluorescent analyses demonstrated that APC and EDD co-localized in the cytoplasm of the cell. Over-expression of EDD enhanced the protein expression level of APC and its binding partner Axin, resulting in inhibition of Wnt signaling downstream of beta-catenin. Conversely, siRNA knock-down of EDD down-regulated APC at the protein level without altering its mRNA level, causing enhanced protein expression of beta-catenin. Thus, through protein-protein interaction, EDD stabilizes APC and up-regulates APC's function to inhibit beta-catenin, suggesting that EDD could act as a colorectal tumor suppressor.

A marked species difference was observed both in vitro and in vivo in the activity of SA446, an orally active inhibitor of angiotensin converting enzyme (ACE), as compared with that of captopril in five different animal species. The activity of SA446 in vitro in inhibiting plasma ACE correlated with the activity in vivo as determined by inhibition of the pressor response to angiotensin I (AI). SA446 was more potent as an inhibitor of AI response in dogs, cats and rabbits than in guinea pigs and rats. Furthermore, ACE activity in whole blood in vivo was inhibited by SA446, and the activity of SA446 was also more potent in dogs than in rats. The concentration of SA446 in the ultrafiltrate of blood (free form) was significantly higher in dogs than in rats, while no difference was observed in level of SA446 in the whole blood (free and protein-bound form) between these two species after intravenous injection. The binding rate of SA446 to plasma protein of rats in vitro was more than twice as high as that of dogs. These results suggest that the difference in the protein binding rate of SA446 is reflected in ultrafiltrate level and is one of the important components in defining the species difference in SA446 action.

The renal excretory mechanism of an orally active inhibitor of angiotensin converting enzyme (SA-446) was examined in anesthetized dogs. Parenteral administration of this compound resulted in production of constant levels of about 2 mg/l in the plasma (PSA) and the urine concentration was 726 +/- 200 mg/l, a level significantly higher than that in the plasma. Renal clearance of SA-446 (CSA) was 2.24 +/- 0.34 ml/g X min and was significantly higher than GFR. The clearance ratio (CSA/GFR) of over 1.0 was indicative of a net tubular secretion. Administration of probenecid resulted in a significant rise in PSA and in a significant decrease in urinary excretion but with no change in the plasma protein binding ratio. CSA decreased significantly from 2.24 +/- 0.34 to 0.71 +/- 0.14 ml/g X min. The inhibitory action of SA-446 (0.02 mg/kg, i.v.) on the pressor response to angiotensin I disappeared at about 50 min, this action being maintained for about 2 h in the probenecid pretreated dog. Since probenecid is a competitive inhibitor of organic anion secretory transport, our results show the net tubular secretion of SA-446, via organic anion transport systems. Prolongation of the action of SA-446, as induced by probenecid may be due to the increase of plasma concentration, by the inhibition of tubular secretion.