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Purpose: Several studies have investigated good communication practices with adult patients receiving bad news about cancer. However, while communication preferences may differ between adults and adolescent and young adult (AYA) patients, these preferences have not been determined for AYA patients. The primary endpoint of this study was to describe the communication preferred by AYA patients with cancer. Methods: The study cohort consisted of 15 patients who received a cancer diagnosis at the age of 15-29 years. Patients were recruited at the National Cancer Center Hospital or through "STAND UP!!," an association of AYA patients with cancer. Semistructured interviews were conducted, and content analysis was performed to analyze the data. Results: For the preferred communication of AYA patients, 80 categories were extracted in the following five domains: (1) "Supportive setting," (2) "Method of disclosure of bad news," (3) "Information given," (4) "Emotional support," and (5) "Support for the patient's decision making." Although more than half of the categories extracted were identical to the preferred communication of adult patients, some categories specific to AYA patients were identified that physicians should consider. Preferences specific to AYA patients included mentioning generation-specific social factors, not showing excessive empathy, and communicating in a manner considering their age and cognitive development that supports their decision making. Conclusion: Although physicians should be mindful of the specific preferences of AYA patients, the basic attitude and communication preferences are similar to those of patients of other generations.

Context: The Quality of Life at the End of Life-Cancer Scale (QUAL-EC) is a self-reported instrument to assesses the quality of life of patients with cancer near the end of life., Objective: To test the reliability and validity of the QUAL-EC-J, a Japanese translated version of the QUAL-EC., Methods: A total of 179 Japanese patients with advanced cancer completed the QUAL-EC-J, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Rosenberg Self-Esteem Scale, Multidimensional Scale of Perceived Social Support, Functional Assessment of Cancer Therapy-General Scale, and Functional Assessment of Chronic Illness Therapy-Spiritual questionnaires. We performed confirmatory factor analysis of the four structures of the QUAL-EC and exploratory factor analysis of the QUAL-EC-J. Internal consistency was assessed using Cronbach's α coefficient and validity was examined by calculating correlations with relevant scales., Results: Confirmatory factor analysis showed an inadequate fit to the original QUAL-EC structure. Exploratory factor analysis revealed a three-factor structure of the QUAL-EC-J, with Cronbach's α values of 0.68-0.88. All subscales were negatively correlated with depression and anxiety. Each subscale was correlated with related measures: "symptom control" with "physical well-being"; "acceptance of disease and life" with "social and family well-being" and "meaning/peace"; and "preparation for end of life" with "emotional well-being" and "meaning/peace.", Conclusions: The QUAL-EC-J has a three-factor structure with acceptable reliability and sufficient validity. Differences in the factor structure between the QUAL-EC-J and the QUAL-EC may be due to cultural factors. Study findings suggest that utilization of the QUAL-EC-J could help to improve research and clinical care in advanced cancer in Japan., (Copyright © 2023 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: A key to success of cancer immunotherapy is the amplification and sustenance of various effector cells. The hallmark of prominent antitumor T cells is their long-term effector function. Although interleukin (IL)-2 is an attractive cytokine, several attempts have been made towards developing IL-2 modalities with improved effectiveness and safety that enhance natural killer (NK) cells or T cells in cancer models. However, whether such IL-2 modalities can simultaneously support long-term innate and adaptive immunity, particularly stem-like memory, has not been shown. To resolve this issue, we compared the antitumor cellular mechanism with two IL-2/anti-IL-2 complexes (IL-2Cxs) administered in combination with a therapeutic cancer vaccine, which we had previously established as an in vivo dendritic cell-targeting therapy., Methods: Two types of IL-2Cxs, CD25-biased IL-2Cx and CD122-biased IL-2Cx, together with a Wilms' tumor 1-expressing vaccine, were evaluated in a leukemic model. The immunological response and synergistic antitumor efficacy of these IL-2Cxs were then evaluated., Results: When CD25-biased or CD122-biased IL-2Cxs in combination with the vaccine were assessed in an advanced-leukemia model, the CD122-biased IL-2Cx combination showed 100% survival, but the CD25-biased IL-2Cx did not. We first showed that invariant natural killer T (NKT) 1 cells are predominantly activated by CD122-biased IL-2Cx. In addition, in-depth analysis of immune responses by CD122-biased IL-2Cx in lymphoid tissues and the tumor microenvironment revealed a dramatic increase in the distinct subsets of NK and CD8 + T cells with stem-like phenotype (CD27 + Sca-1 hi , CXCR3 hi , CD127 + TCF-1 + T-bet + Eomes + ). Moreover, CD122-biased IL-2Cx combination therapy maintained long-term memory CD8 + T cells capable of potent antitumor protection. After the high dimensional profiling analysis of NK and CD8 + T cells, principal component analysis revealed that the stem-like-NK cell and stem-like-CD8 + T cell state in the combination were integrated in the same group., Conclusions: CD122-biased IL-2Cx combined with the vaccine can induce a series of reactions in the immune cascade, including activation of not only NKT1 cells, but also NK and CD8 + T cells with a stem-like memory phenotype. Since it can also lead to a long-term, strong antitumor response, the combination of CD122-biased IL-2Cx with a vaccine may serve as a potential and competent strategy for patients with advanced cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Both natural killer T (NKT) and natural killer (NK) cells are innate cytotoxic lymphoid cells that produce inflammatory cytokines and chemokines, and their role in the innate immune response to tumors and microorganisms has been investigated. Especially, emerging evidence has revealed their status and function in the tumor microenvironment (TME) of tumor cells. Some bacteria producing NKT cell ligands have been identified to exert antitumor effects, even in the TME. By contrast, tumor-derived lipids or metabolites may reportedly suppress NKT and NK cells in situ. Since NKT and NK cells recognize stress-inducible molecules or inhibitory molecules on cancer cells, their status or function depends on the balance between inhibitory and activating receptor signals. As a recent strategy in cancer immunotherapy, the mobilization or restoration of endogenous NKT or NK cells by novel vaccines or therapies has become a focus of research. As a new biological evidence, after activation, effector memory-type NKT cells lasted in tumor-bearing models, and NK cell-based immune checkpoint inhibition potentiated the enhancement of NK cell cytotoxicity against cancer cells in preclinical and clinical trials. Furthermore, several new modalities based on the characteristics of NKT and NK cells, including artificial adjuvant vector cells, chimeric antigen receptor-expressing NK or NKT cell therapy, or their combination with immune checkpoint blockade have been developed. This review examines challenges and future directions for improving these therapies.

Objective: Preventing postoperative delirium with agitation is vital in the older population. We examined the preventive effect of yokukansan on postoperative delirium with agitation in older adult patients undergoing highly invasive cancer resection., Methods: We performed a secondary per-protocol analysis of 149 patients' data from a previous clinical trial. Patients underwent scheduled yokukansan or placebo intervention 4-8 days presurgery and delirium assessment postoperatively. Delirium with agitation in patients aged ≥75 years was assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and the Japanese version of the Delirium Rating Scale-Revised-98. We assessed odds ratios for yokukansan (TJ-54) compared with placebo for the manifestation of postoperative delirium with agitation across patients of all ages (n = 149) and those aged ≥65 years (n = 82) and ≥ 75 years (n = 21) using logistic regression., Results: Delirium with agitation manifested in 3/14 and 5/7 patients in the TJ-54 and placebo groups, respectively, among those aged ≥75 years. The odds ratio for yokukansan vs. placebo was 0.11 (95% confidence interval: 0.01-0.87). An age and TJ-54 interaction effect was detected in patients with delirium with agitation. No intergroup differences were observed in patients aged ≥65 years or across all ages for delirium with agitation., Conclusions: This is the first study investigating the preventive effect of yokukansan on postoperative delirium with agitation in older adults. Yokukansan may alleviate workforce burdens in older adults caused by postoperative delirium with agitation following highly invasive cancer resection., (© The Author(s) 2022. Published by Oxford University Press.)

The efficacy of current coronavirus disease 2019 (COVID-19) vaccines has been demonstrated; however, emerging evidence suggests insufficient protection in certain immunocompromised cancer patients. We previously developed a cell-based anti-cancer vaccine platform involving artificial adjuvant vector cells (aAVCs) capable of inducing a strong adaptive response by enhancing the innate immunity. aAVCs are target antigen-transfected allogenic cells that simultaneously express the natural killer T-cell ligand-CD1d complex on their surface. In the present study, we applied this system for targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (CoV-2-S) using CoV-2-S-expressing aAVCs (aAVC-CoV-2) and evaluated the immune response in a murine model. A single dose of aAVC-CoV-2 induced a large amount of CoV-2-S-specific, multifunctional CTLs in addition to CD4 + T-cell-dependent anti-CoV-2-S-specific Abs. CoV-2-S-specific CTLs infiltrated the lung parenchyma and persisted as long-term memory T cells. Furthermore, we immunized mice with CoV-2-S- and tumor-associated antigen (TAA)-co-expressing aAVCs (aAVC-TAA/CoV-2) and evaluated whether the anti-SARS-CoV-2 and antitumor CTLs were elicited. We found that the aAVC-TAA/CoV-2-S therapy exerted apparent antitumor effects and induced CoV-2-S-specific CTLs. These findings suggest aAVC-TAA/CoV-2-S therapy as a promising vaccine candidate for preventing COVID-19, as well as enhancing the effectiveness of cancer therapies., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The usefulness of depression scales for patients with cancer based on item response theory (IRT) and computer adaptive testing (CAT) has not yet been fully explored. This study thus aimed to develop an IRT-based tool for measuring depression in patients with cancer. We analyzed data from 393 patients with cancer from four tertiary centers in Japan who had not received psychiatric treatment. They answered 62 questions across five categories regarding their psychiatric status over the previous week. We selected 28 items that satisfied the assumptions of IRT, fitted a graded response model to these items, and performed CAT simulations. The CAT simulation used an average of 6.96 items and showed a Pearson's correlation coefficient of 0.916 (95% confidence interval, 0.899-0.931) between the degree of depression estimated by simulation and that estimated using all 28 items. The measurement precision of CAT with only four items was superior to that of the estimation using the calibrated Patient Health Questionnaire-9. These results imply that this scale is useful and accurate for measuring depression in patients with cancer., (© 2022. The Author(s).)

Lymphocyte activation gene-3 (LAG-3) is a potent inhibitory co-receptor; yet, its functional ligand remains elusive, with distinct potential ligands identified. Here, we investigated the relative contribution of potential ligands, stable peptide-MHC class II complexes (pMHCII) and fibrinogen-like protein 1 (FGL1), to LAG-3 activity in vitro and in vivo. Binding of LAG-3 to stable pMHCII but not to FGL1 induced T cell suppression in vitro. Consistently, LAG-3 mutants lacking FGL1-binding capacity but not those lacking stable pMHCII-binding capacity retained suppressive activity in vitro. Accordingly, targeted disruption of stable pMHCII- but not FGL1-binding capacity of LAG-3 in NOD mice recapitulated diabetes exacerbation by LAG-3 deficiency. Additionally, the loss of stable pMHCII-binding capacity of LAG-3 augmented anti-cancer immunity comparably with LAG-3 deficiency in C57BL/6 mice. These results identify stable pMHCII as a functional ligand of LAG-3 both in autoimmunity and anti-cancer immunity. Thus, stable pMHCII-LAG-3 interaction is a potential therapeutic target in human diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Managing Cancer and Living Meaningfully (CALM) is a novel, brief and manualised psychotherapeutic intervention intended to treat and prevent depression and end-of-life distress in patients with advanced cancer. This phase 2 trial aims to assess the feasibility and preliminary efficacy of CALM in Japanese patients with cancer., Methods and Analysis: This study is a single-arm clinical trial. All patients involved in the study are ≥18 years of age, have been diagnosed with advanced or metastatic solid-tumour cancer, and their expected survival is at least 6 months. CALM comprises three to six individual therapy sessions, each lasting approximately 45-60 min, provided over 3- 6 months. The participants will be asked to complete questionnaires at baseline (t0), 3 months (t1) and 6 months (t2). The primary outcomes are rates of completion of the intervention and of the outcome measures and improvement of depressive symptoms measured using the Patient Health Questionnaire-9 between t0 and t2. The criteria for the successful rate of completion is that at least 70% participants who participate in at least three sessions will complete measures at t2. The secondary outcomes are the improvement in scores on: (1) the Quality of Life at the End of Life-Cancer Scale, (2) the Experiences in Close Relationships scale, (3) the Death and Dying Distress Scale and (4) the Clinical Evaluation Questionnaire., Ethics and Dissemination: This study was approved by the Research Ethics Committee of The University of Tokyo, Cancer Institute Hospital of Japanese Foundation for Cancer Research and Yamaguchi University. We will conduct the study in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects. The results of this study will be submitted for peer-reviewed publication and presentation at local, national and international scientific meetings and conferences., Trail Registration Number: UMIN000040032; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Targeted blockade of the checkpoint molecule programmed cell death 1 (PD-1) can activate tumor-specific T cells to destroy tumors, whereas targeted potentiation of PD-1 is expected to suppress autoreactive T cells and alleviate autoimmune diseases. However, the development of methods to potentiate PD-1 remains challenging. Here we succeeded in eliciting PD-1 function by targeting the cis-PD-L1-CD80 duplex, formed by binding of CD80 to the PD-1 ligand PD-L1, that attenuates PD-L1-PD-1 binding and abrogates PD-1 function. By generating anti-CD80 antibodies that detach CD80 from the cis-PD-L1-CD80 duplex and enable PD-L1 to engage PD-1 in the presence of CD80, we demonstrate that the targeted dissociation of cis-PD-L1-CD80 duplex elicits PD-1 function in the condition where PD-1 function is otherwise restricted. We demonstrate using murine models that the removal of PD-1 restriction is effective in alleviating autoimmune disease symptoms. Our findings establish a method to potentiate PD-1 function and propose the removal of restraining mechanisms as an efficient strategy to potentiate the function of inhibitory molecules., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The clinical benefits of immune checkpoint blockage (ICB) therapy have been widely reported. In patients with cancer, researchers have demonstrated the clinical potential of antitumor cytotoxic T cells that can be reinvigorated or enhanced by ICB. Compared to self-antigens, neoantigens derived from tumor somatic mutations are believed to be ideal immune targets in tumors. Candidate tumor neoantigens can be identified through immunogenomic or immunopeptidomic approaches. Identification of neoantigens has revealed several points of the clinical relevance. For instance, tumor mutation burden (TMB) may be an indicator of immunotherapy. In various cancers, mutation rates accompanying neoantigen loads may be indicative of immunotherapy. Furthermore, mismatch repair-deficient tumors can be eradicated by T cells in ICB treatment. Hence, immunotherapies using vaccines or adoptive T-cell transfer targeting neoantigens are potential innovative strategies. However, significant efforts are required to identify the optimal epitopes. In this review, we summarize the recent progress in the identification of neoantigens and discussed preclinical and clinical studies based on neoantigens. We also discuss the issues remaining to be addressed before clinical applications of these new therapeutic strategies can be materialized.

The anti-apoptotic myeloid cell leukemia 1 (MCL1) protein belongs to the pro-survival BCL2 family and is frequently amplified or elevated in human cancers. MCL1 is highly unstable, with its stability being regulated by phosphorylation and ubiquitination. Here, we identify acetylation as another critical post-translational modification regulating MCL1 protein stability. We demonstrate that the lysine acetyltransferase p300 targets MCL1 at K40 for acetylation, which is counteracted by the deacetylase sirtuin 3 (SIRT3). Mechanistically, acetylation enhances MCL1 interaction with USP9X, resulting in deubiquitination and subsequent MCL1 stabilization. Therefore, ectopic expression of acetylation-mimetic MCL1 promotes apoptosis evasion of cancer cells, enhances colony formation potential, and facilitates xenografted tumor progression. We further demonstrate that elevated MCL1 acetylation sensitizes multiple cancer cells to pharmacological inhibition of USP9X. These findings reveal that acetylation of MCL1 is a critical post-translational modification enhancing its oncogenic function and provide a rationale for developing innovative therapeutic strategies for MCL1-dependent tumors., Competing Interests: Declaration of interests W.W. is a co-founder and consultant for ReKindle Therapeutics., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Context: No standard preventive or therapeutic methods have been established for preoperative anxiety and postoperative delirium in patients with cancer., Objectives: To clarify the therapeutic effect of yokukansan for perioperative psychiatric symptoms in patients with cancer as well as to confirm its safety profile., Methods: This is a randomized, double-blind, and placebo-controlled trial conducted at a single center in Tokyo, Japan. About 195 patients with cancer scheduled to undergo tumor resection took one packet of the study drug, which was administered orally. Coprimary outcomes were change in preoperative anxiety assessed with the Hospital Anxiety and Depression Scale-Anxiety and incidence of postoperative delirium assessed with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Interim analysis was performed with one-third (n = 74) of the target number of registered patients., Results: Because this trial was canceled based on the results of the interim analysis and the protocol treatment was discontinued in patients who were already registered, conclusions were based on the full analysis set of 160 participants. There were no significant differences between groups in the change of mean Hospital Anxiety and Depression Scale-Anxiety score (intervention group [SD] 0.4 [3.0] vs. placebo group 0.5 [3.0]; P = 0.796) or the incidence of postoperative delirium (32% vs. 30%; P = 0.798). There were no serious adverse events in either group., Conclusion: In patients with cancer undergoing highly invasive surgeries, yokukansan demonstrated no significant efficacy for the treatment of preoperative anxiety or the prevention of postoperative delirium. Yokukansan is already used in daily practice in Japan, but we should be careful with its future use., (Copyright © 2020. Published by Elsevier Inc.)

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis.

The biochemical composition of processed ascites is not well researched and may differ among institutions. This prospective study was conducted to evaluate the biochemical characteristics of processed ascites of 11 patients with liver cirrhosis and carcinoma who underwent cell-free and concentrated ascites reinfusion therapy. The ascites due to carcinoma were more acidic and had higher lactate dehydrogenase activity than those due to liver cirrhosis. The ascites due to liver cirrhosis contained a higher amount of immunoglobulin than those due to carcinoma. Immunoglobulin preparations were approximately 2.95% IgG in liver cirrhosis ascites and 2.25% IgG in carcinoma ascites. Moreover, the concern about IgA infusion in the patient with IgA deficiency made it important to identify the source of the ascites. The present study provided fundamental information regarding the safety of cell-free and concentrated ascites reinfusion therapy., (© 2020 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Targeted blockade of programmed cell death 1 (PD-1), an immune-checkpoint receptor that inhibits T cell activation, provides clinical benefits in various cancers. However, how PD-1 modulates gene expression in T cells remains enigmatic. Here we investigated how PD-1 affects transcriptome changes induced by T cell receptor (TCR) activation. Intriguingly, we identified a huge variance in PD-1 sensitivity among TCR-inducible genes. When we quantified the half maximal effective concentration (EC 50 ) as the relationship between change in gene expression and TCR signal strength, we found that genes associated with survival and proliferation were efficiently expressed upon TCR activation and resistant to PD-1-mediated inhibition. Conversely, genes encoding cytokines and effector molecules were expressed less efficiently and sensitive to PD-1-mediated inhibition. We further demonstrated that transcription factor binding motifs and CpG frequency in the promoter region affect EC 50 and thus the PD-1 sensitivity of genes. Our findings explain how PD-1, dependent on the TCR signal strength, calibrates cellular transcriptomes to shape functional properties of T cell populations., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2019 Elsevier Inc. All rights reserved.)

One of the primary goals in tumor immunotherapy is to reset the immune system from tolerogenic to immunogenic - a process in which invariant natural killer T (iNKT) cells are implicated. iNKT cells develop in the thymus and perform immunosurveillance against tumor cells peripherally. When optimally stimulated, iNKT cells differentiate and display more efficient immune functions. Some cells survive and act as effector memory cells. We discuss the putative roles of iNKT cells in antitumor immunity, and posit that it may be possible to develop novel therapeutic strategies to treat cancers using iNKT cells. In particular, we highlight the challenge of uniquely energizing iNKT cell-licensed dendritic cells to serve as effective immunoadjuvants for both arms of the immune system, thus coupling immunological networks., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Targeted blockade of PD-1 with immune checkpoint inhibitors can activate T cells to destroy tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of T cell responses, yet how PD-1 function is restricted at the activation stage is currently unknown. Here we demonstrate that CD80 interacts with PD-L1 in cis on antigen-presenting cells (APCs) to disrupt PD-L1/PD-1 binding. Subsequently, PD-L1 cannot engage PD-1 to inhibit T cell activation when APCs express substantial amounts of CD80. In knock-in mice in which cis -PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1. These findings indicate that CD80 on APCs limits the PD-1 coinhibitory signal, while promoting CD28-mediated costimulation, and highlight critical components for induction of optimal immune responses., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: It has been noted that not only adverse psychosocial health effects but also mortality might increase for a person living with a spouse with cancer. This study examined the association between a partner's cancer diagnosis and mortality among a Japanese population., Methods: In December 2006, a survey was conducted on participants aged 40 years or older who were residing in northeastern Japan. We identified couples using municipality-specific household ID numbers by searching public records and confirmed partner's cancer diagnosis after the baseline measurement using regional cancer registration information. After following up for a maximum of 4.0 years with the participants regarding mortality and emigration by reviewing the Residential Registry Record, we used Cox's proportional hazards regression to estimate the hazard ratio (HR) of all-cause mortality., Results: We identified 25,938 participants (12,969 pairs) and included them in the analyses. A total of 1,308 (5.0%) participants had partners with a cancer diagnosis after baseline. The study found no association between a partner's cancer diagnosis and all-cause mortality; multivariable HRs of all-cause mortality for individuals in exposed subjects compared with those in unexposed subjects were 1.35 (95% confidence interval [CI] = 0.99-1.83; p = .055). Contrarily, sensitivity analyses of mortality attributed to having partners diagnosed with cancer based on the time since entry showed that all-cause mortality significantly increased only within one year from spouse cancer diagnosis; HR = 2.18 (95% CI = 1.44-3.30; p < .01)., Conclusions: Our findings reveal that the mortality rate from partner's cancer diagnosis was significantly high during the early period of diagnosis and multidisciplinary teams for cancer treatment might be important for preventing death among the partner.

Background: Preoperative anxiety and postoperative delirium affect both short- and long-term prognoses in patients with cancer; therefore, these conditions require early prevention and treatment. However, no standard preventive or therapeutic methods have been established for them. Yokukansan, a Japanese herbal medicine for the treatment of insomnia and anxiety, causes relatively few adverse drug reactions and effectively improves the behavioral and psychological symptoms of dementia. Thus, it is expected to be useful for treating and/or preventing perioperative psychiatric symptoms in patients with cancer. The objective of this study is to clarify the therapeutic effect of Yokukansan for preoperative anxiety and its preventive effect on postoperative delirium in cancer patients, as well as to confirm its safety profile., Methods: This study is a randomized, double-blind, placebo-controlled study in cancer patients scheduled to undergo tumor resection. Patients who provide consent are randomly allocated to receive oral administration of Yokukansan or placebo, and study drug administration is continued for 4 days or longer prior to surgery. We defined two primary endpoints, change in preoperative anxiety and incidence of postoperative delirium. Secondary endpoints are severity score of postoperative delirium, duration of postoperative delirium, amount of benzodiazepines used prior to surgery, amount of antipsychotic agents used after surgery, and number of postoperative hospitalization days. We plan to complete the analysis on March 31, 2021. The target number of registered patients is 110 per group, or 220 in total., Discussion: This study is the first randomized, double-blind, placebo-controlled study intended to clarify the effects of a Japanese herbal medicine, Yokukansan, in the prevention and treatment of perioperative psychiatric symptoms in patients with cancer. The trial was initiated on August 14, 2017, with 195 subjects randomized by October 5, 2018., Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR), UMIN000027561 . Registered on 31 May 2017.

Background: Postoperative delirium is a common and important complication in cancer patients. We need to identify patients at high risk of postoperative delirium such that it can be prevented preoperatively or in early postoperative phase. The aim of this study was to investigate whether preoperative anxiety predicted onset of postoperative delirium in cancer patients, not only in order to identify high-risk groups but also to help develop new preventive approaches., Methods: This was a prospective observational cohort study of cancer patients undergoing tumor resections. Postoperative delirium was assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Preoperative anxiety was evaluated with the Hospital Anxiety and Depression Scale-Anxiety (HADS-A), and we defined HADS-A > 7 as clinical anxiety. We conducted multivariate logistic regression to determine which factors were predictors of delirium., Results: The final analysis included 91 patients, 29 of whom met the criteria for postoperative delirium. In multivariable logistic regression, age (5-year increments; odds ratio (OR) = 1.565, 95% confidence interval (CI) = 1.057-2.317, p = 0.025) and HADS-A > 7 (OR = 4.370, 95% CI = 1.051-18.178, p = 0.043) predicted delirium onset. These variables explained 74.2% of the variance., Conclusions: Preoperative anxiety strongly predicted postoperative delirium in cancer patients. Our findings suggest that preoperative anxiety may be a new target for prevention of postoperative delirium. Trial registration number This study was registered at UMIN000018980.

Purpose: We explored pediatricians' practices and attitudes concerning end-of-life discussions (EOLds) with pediatric patients with cancer, and identified the determinants of pediatricians' positive attitude toward having EOLds with pediatric patients., Methods: A multicenter questionnaire survey was conducted with 127 pediatricians specializing in the treatment of pediatric cancer., Results: Forty-two percent of participants reported that EOLds should be held with the young group of children (6-9 years old), 68% with the middle group (10-15 years old), and 93% with the old group (16-18 years old). Meanwhile, 6, 20, and 35% of participants answered that they "always" or "usually" discussed the incurability of the disease with the young, middle, and old groups, respectively; for the patient's imminent death, the rates were 2, 11, and 24%. Pediatricians' attitude that they "should have" EOLds with the young group was predicted by more clinical experience (odds ratio [OR] 1.077; p = 0.007), more confidence in addressing children's anxiety after EOLd (OR 1.756; p = 0.050), weaker belief in the demand for EOLd (OR 0.456; p = 0.015), weaker belief in the necessity of the EOLd for children to enjoy their time until death (OR, 0.506; p = 0.021), and weaker belief in the importance of maintaining a good relationship with the parents (OR 0.381; p = 0.025)., Conclusions: While pediatricians nearly reached consensus on EOLds for the old group, EOLds with the young group remain a controversial subject. While pediatricians who supported EOLds believed in their effectiveness or necessity, those who were against EOLds tended to consider the benefits of not engaging in them.

Most tumors employ multiple strategies to attenuate T-cell-mediated immune responses. In particular, immune suppression surrounding the tumor is achieved by interfering with antigen-presenting cells and effector T cells. Controlling both the tumor and the tumor microenvironment (TME) is critical for cancer treatment. Checkpoint blockade therapy can overcome tumor-induced immune suppression, but more than half of the patients fail to respond to this treatment; therefore, more effective cancer immunotherapies are needed. Generation of an anti-tumor immune response is a multi-step process of immune activation against the tumor that requires effector T cells to recognize and exert toxic effects against tumor cells, for which two strategies are employed-inhibition of various types of immune suppressor cells, such as myeloid cells and regulatory T cells, and establishment of anti-tumor immune surveillance including, activation of natural killer cells and cytotoxic T cells. It was recently shown that anti-cancer drugs not only directly kill tumor cells, but also influence the immune response to cancer by promoting immunogenic cell death, enhancing antigen presentation or depleting immunosuppressive cells. Herein, we review the mechanisms by which tumors exert immune suppression as well as their regulation. We then discuss how the complex reciprocal interactions between immunosuppressive and immunostimulatory cells influence immune cell dynamics in the TME. Finally, we highlight the new therapies that can reverse immune suppression in the TME and promote anti-tumor immunity.

FBW7 is one of the most well characterized F-box proteins that serve as substrate recognition subunits of SCF (Skp1-Cullin 1-F-box proteins) E3 ubiquitin ligase complexes. SCF FBW7 plays key roles in regulating cell cycle progression, differentiation, and stem cell maintenance largely through targeting a broad range of oncogenic substrates for proteasome-dependent degradation. The identification of an increasing number of FBW7 substrates for ubiquitination, and intensive in vitro and in vivo studies have revealed a network of signaling components controlled by FBW7 that contributes to metabolic regulation as well as its tumor suppressor role. Here we mainly focus on recent findings that highlight a critical role for FBW7 in cancer and metabolism., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Phenotype-based analysis of circulating tumor cells (CTCs) is a promising approach to identification of new therapeutic targets and to elucidation of the biological properties. Nonetheless, ex vivo culturing of CTCs is still a technical challenge. Here, we develop a novel ex vivo culture method for CTCs using a fibroblast feeder layer and a magnetic coculture protocol. CTCs in the blood of a mouse metastasis model are labeled magnetically with magnetite nanoparticles. The labeled CTCs are isolated by a magnetic capture column and a size-selective capture filter. The isolated CTCs are positioned on a fibroblast feeder layer by the magnetic force. As a result, we observe adhesion and proliferation of the CTCs under the conditions of the fibroblast feeder layer and the magnetic force, whereas no adhesion or proliferation is observed without the feeder layer. After that, we culture the CTCs and obtain three CTC-derived cell lines. Using these cell lines, we perform phenotype-based analyses of invasiveness and drug resistance and find that the CTC-derived cell lines are more malignant than the original cells. Thus, the proposed method would be a promising approach to ex vivo culture of CTCs for phenotype-based analysis, and possibly used in cancer treatment., (Copyright © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: In Japan, commercially delivered FDG is manufactured in three batches per day at fixed constant activity and distributed in vials. Consequently, the amount of activity administered to the patient varies depending on the timing of injection. We evaluated a method for adjusting the scan time according to the body mass index (BMI) to obtain equivalent image quality for every patient., Methods: We examined a total of 301 routine clinical oncology PET scans using commercially delivered FDG. The relation between the injected activity and the noise equivalent count per scan length (NECpatient) was evaluated as a marker of image quality; its association with BMI was also examined., Results: The injected activity and NECpatient exhibited large variations (230.4 ± 55.8 MBq and 19.9 ± 2.9 Mcounts/m). There was a weak correlation between the injected activity and NECpatient (r ~ 0.3) for thin patients (BMI < 21 kg/m(2)), but no correlation for patients with higher BMIs. However, a significant correlation was found between BMI and NECpatient (p < 0.0001)., Conclusion: In a community hospital using commercially delivered FDG, it is possible to reduce the variability of the NECpatient and obtain uniform image quality by changing the scan time as a function of patient BMI, even with uncontrollable injected activity.

A new oxygenated lanostane-type triterpene, named lucidumol C, together with six known compounds, was isolated from the chloroform extract of the fruiting bodies of Ganoderma lingzhi. Structures were established based on extensive spectroscopic and chemical studies. Potential cytotoxic activities of the isolated compounds were evaluated against human colorectal carcinoma (HCT-116, Caco-2), human liver carcinoma (HepG2), and human cervical carcinoma (HeLa) cell lines using WST-1 reagent. Selectivity was evaluated using normal human fibroblast cells (TIG-1 and HF19). Among the compounds, lucidumol C showed potent selective cytotoxicity against HCT-116 cells with an IC50 value of 7.86 ± 4.56 µM and selectivity index (SI) >10 with remarkable cytotoxic activities against Caco-2, HepG2 and HeLa cell lines.

Objective: The quality-adjusted life year, which is usually calculated from the health utility value, is now a standard measurement used in political decision-making in health. Although depression is the leading cause of decrement in health utility in general population, impact of comorbid depression among cancer patients has not been studied sufficiently. Therefore, this study aimed to measure the impact of depression on cancer patients' health utility score, according to the severity of depression., Methods: Impact of depression severity (measured by the Patient Health Questionnaire) on health utility score (measured by the EuroQoL-5 scale) was evaluated in a sample of 328 Japanese cancer patients, controlling for performance status, symptom burden, and demographic variables., Results: The patients with depression had significantly lower health utility value than those without depression (mean decrement = 0.14). Decrements in health utility of 0.13, 0.18, and 0.19 were observed for mild, moderate, and moderately severe to severe level of depression, respectively. The difference was significant between groups. Depression severity was a significant predictor for health utility (standardized coefficient beta = -0.25), which was comparable with physical symptom burden and performance status. Participants' age, gender, cancer stage, and comorbid illness were not significant. The model explained 37.9% of the variance., Conclusions: Even mild level of depression caused clinically meaningful decrement in health utility value in cancer patients, which was comparable with decrements due to major physical complications of cancer. Influence of depression should be carefully investigated when interpreting the quality-adjusted life year among cancer patients. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

Context: There is controversy around the association between depressive symptoms and age in adult cancer patients., Objectives: The aim of this study was to evaluate the following hypotheses: 1) cancer patients' depressive symptoms decrease with age, and 2) in individuals aged 65 years or older, depressive symptoms increase because of the effect of somatic symptoms., Methods: We retrospectively analyzed a database of 356 cancer patients who were consecutively recruited in a previous multicenter cross-sectional study. Depressive symptoms were assessed by the Patient Health Questionnaire-9 (PHQ-9), and correlations with age and other factors were assessed by hierarchical multivariate regression analysis. Age was entered as the dependent variable in the first step, patient characteristics and cancer-related variables were entered in the second step, and somatic symptoms were entered in the last step. We analyzed this model for both the total sample and the subpopulation aged 65 years or older., Results: In the total sample, the PHQ-9 score was significantly associated with lower age, fatigue, and shortness of breath (adjusted R(2) 14.2%). In the subpopulation aged 65 years or older, no factor was associated with the PHQ-9 score (adjusted R(2) 7.3%)., Conclusion: The finding that depressive symptoms in cancer patients decreased with age was concordant with our first hypothesis, but the second hypothesis was not supported. Younger cancer patients were vulnerable to depressive symptoms and should be monitored carefully. Further studies using more representative samples are needed to examine in detail the association between depressive symptoms and age in older cancer patients., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

For patients with advanced cancer and their families, it is a challenge to adapt to their difficult situation. They have the potential power to do so, and medical staff can keep on supporting them to promote the process. Medical staff should not be afraid to relate to patients, and should adopt a flexible approach in parallel with patients' needs.

Objective: End-of-life discussions with patients can be one of the most difficult and stressful tasks for the oncologist. However, little is known about the discussions that healthcare providers have with patients in such situations and the difficulties they face. The primary end points of this study were to describe the contents of end-of-life discussion in the pediatric setting and the barriers to end-of-life discussion for pediatric patients, as perceived by pediatric healthcare providers., Methods: Participants were 10 healthcare providers. Semi-structured interviews were conducted, and the KJ method was performed to analyze the data., Results: We found 23 barriers against end-of-life discussion with pediatric cancer patients. These barriers were classified as follows: healthcare provider factors, patient factors, parent factors and institutional or cultural factors. In addition to barriers found in previous studies, some unique barriers were uncovered such as, 'Lack of confidence to face the patient after the discussion', 'Uncertain responsibility for treatment decision-making' and 'No compelling reason to discuss'. Healthcare providers actively discussed the purpose of treatment and the patients' wishes and concerns; however, they were reluctant to deal with the patients' own impending death and their estimated prognosis., Conclusions: End-of-life discussion with pediatric patients differs from that with adult patients. Further studies are required to analyze pediatric cases associated with end-of-life discussion and carefully discuss its adequacy, pros and cons., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Despite some clinical guidelines for incorporating integrated psychosocial care (combining psychological screening and psychological intervention, including adequate collaboration with mental health specialists) into routine oncology practice, definitive empirical evidence regarding the effectiveness of such care remains unavailable. Here the findings of recent experimental studies are reviewed to provide guidance regarding this issue., Methods: Comparative studies examining integrated psychosocial care were reviewed., Results: Studies examining interventions that include both screening and psychological care have produced contradictory results regarding effectiveness, but all the studies that have examined the effect of psychological care after the identification of distress using systematic screening have shown positive results., Conclusions: Integrated psychosocial care may affect patients with significant distress, but the adequacy of introducing such care into routine oncology practice remains debatable.

Objective: Few cancer physicians routinely provide bereavement follow-up in clinical practice. The purpose of this study was to identify the prevalence of impaired mental health among the bereaved spouses over several years and explore the indicators for early detection of high-risk spouses during end-of life (EOL) care., Methods: A cross-sectional mail survey was conducted for the bereaved spouses of patients who had died at the National Cancer Center Hospital of Japan. Bereaved spouses with potential psychiatric disorders were identified by the cut-off score of the 28-item General Health Questionnaire. Associated factors of potential psychiatric disorders were explored by logistic regression analysis., Results: A total of 821 spouses experiencing bereavement from 7 months to 7 years returned the questionnaires. Overall mean prevalence of potential psychiatric disorders was 44% (360/821). Bereaved spouses 'under 55 years' (71%) or '2 years after bereavement' (59%) revealed a significantly higher prevalence (p < 0.01). Associated factors during EOL care were several characteristics such as 'spouses' history of psychiatric disorder (odds ratio (OR) = 3.19), 'patients' with stomach cancer (OR = 1.87), and 'patients' using psychiatric consultation services (OR = 1.52) as well as spouses' dissatisfaction with EOL care such as 'physicians' treatment of physical symptoms' (OR = 3.44) and 'time spent communicating with patients' (OR = 1.55)., Conclusions: Nearly half the bereaved spouses showed potential psychiatric disorders even 7 years after bereavement. Patients' psychological distress, spouses' history of psychiatric disorder, and dissatisfaction with EOL care were indicators of high-risk spouses., (Copyright © 2012 John Wiley & Sons, Ltd.)

Aurora kinases and cyclin-dependent kinases, which play critical roles in the cell cycle and are frequently overexpressed in a variety of tumors, have been suggested as attractive targets for cancer therapy. JNJ-7706621, a recently identified dual inhibitor of these kinases, is reported to induce cell cycle arrest, endoreduplication, and apoptosis. In the present study, we further investigated the molecular mechanisms underlying these effects. The inhibitor arrested various cells at G2 phase at low concentration, and at both G1 and G2 phases at high concentration. JNJ-7706621 did not prevent localization of Aurora A to the spindle poles, but did inhibit other centrosomal proteins such as TOG, Nek2, and TACC3 in early mitotic phase. Similarly, the drug did not prevent localization of Aurora B to the kinetochore, but did inhibit other chromosomal passenger proteins such as Survivin and INCENP. In the cells exposed to JNJ-7706621 after nocodazole release, Aurora B, INCENP, and Survivin became relocated to the peripheral region of chromosomes, but Plk1 and Prc1 were localized on microtubules in later mitotic phase. Treatment of nocodazole-synchronized cells with JNJ-7706621 was able to override mitotic arrest by preventing spindle checkpoint signaling, resulting in failure of chromosome alignment and segregation. Injection of the drug significantly inhibited the growth of TC135 Ewing's sarcoma cells transplanted into athymic mice by cell cycle arrest and apoptosis. JNJ-7706621 is a unique inhibitor regulating cell cycle progression at multiple points, suggesting that it could be useful for cell cycle analysis and therapy of various cancers, including Ewing's sarcoma.

Objective: Collaboration between psychiatry and palliative medicine has the potential to enhance the quality of medical practice. The integration between palliative care and psychiatry has been attempted only in discrete medical settings and is not yet firmly established as an institution. Our objective was to determine the availability and degree of integration between psychiatric consultation-liaison services and palliative care in Japan., Methods: A survey questionnaire was mailed to consultation-liaison psychiatrists at 375 government-designated cancer hospitals regarding their consultation-liaison services., Results: A total of 375 survey questionnaires were sent to consultation-liaison psychiatrists, with a response rate of 64.8%. Designated cancer hospitals with approved palliative care teams were significantly more likely to have a consultation-liaison psychiatrist in the palliative care team than those in non-approved palliative care teams [80/80 (100%) versus 110/153 (73%); P= 0.008]. Approved palliative care teams had double the number of referrals, conducted rounds more frequently and held conferences more frequently. Psychiatrists of the approved palliative care teams spent more of their time on palliative care consultations, adhered more closely to consultation processes and contributed more actively to the integration of developmental perspectives in treatment plans., Conclusions: In Japan, most designated cancer hospitals with approved palliative care teams were more likely to integrate psychiatric consultation-liaison services into their palliative care programs. Systematic strategies for integration between palliative care and consultation-liaison psychiatry would contribute to the provision of appropriate psychosocial care for cancer patients and families at all stages.

Objective: Major depressive disorder (MDD) and adjustment disorder (AD) are common psychiatric disorders in cancer patients but are often overlooked in clinical oncology settings. We introduced a clinical screening program utilizing the Distress and Impact Thermometer (DIT) to identify MDD and AD in cancer outpatients receiving chemotherapy. This study assessed the usefulness of the screening program., Methods: Pharmacists administered the DIT to consecutive patients undergoing chemotherapy at an outpatient clinic. Psychiatric treatment was recommended to all the patients with positive screening results. The proportion of patients referred to the Psychiatric Service during the program period was then compared with that during a usual care period., Results: Of the 520 patients who started chemotherapy during the 6-month program period, 5.0% (26/520) were referred to the Psychiatric Service and 2.7% (15/520) were diagnosed as having MDD or AD. No statistically significant difference in the referral rates was observed between the two periods (2.7 vs 1.0%, p = 0.46). However, the period from the first chemotherapy treatment until the visit to the Psychiatric Service was significantly shorter during the program period than during the period of usual care (12.9±13.2 days vs 55.6±17.6 days, p<0.001)., Conclusions: The proportion of patients referred to the Psychiatric Service for the treatment of MDD or AD during the program period was not different from that during the usual care period. However, the program was useful for introducing psychiatric treatment at an earlier stage. Further modifications to the program to improve the referral rate are necessary., (Copyright © 2011 John Wiley & Sons, Ltd.)

Context: Although adjustment disorders (ADs) are common among patients with cancer and such patients are frequently referred to consultation-liaison psychiatrists, little is known about the clinical courses of these patients., Objectives: The present study investigated treatment response to psychiatric intervention and predictors of response in a relatively large sampling of cancer patients with ADs., Methods: We created a database of all referral cases with ADs that included data on the patients' demographic and medical factors and physician-rated Clinical Global Impression (CGI) scale to assess treatment response and clinical course. A CGI-Improvement scale score of better than "much improved" was regarded as indicating a response to treatment; the number of patients who responded to treatment during a four-week follow-up period was assessed. Also, predictors of treatment response were explored by examining demographic and medical factors using a multivariate analysis., Results: Among the 238 eligible patients, 136 (57.1%) responded to psychiatric treatment; most of these responders improved to a subthreshold level of illness. On the other hand, 56 patients (23.5%) did not respond to psychiatric treatment, seven patients (2.9%) developed major depressive disorders, and 39 patients (16.4%) discontinued treatment before achieving a response. Among the predictive factors that were explored, suffering from pain significantly predicted a good treatment response, whereas a worse performance status predicted a poor treatment response., Conclusion: Cancer patients with ADs can respond to psychiatric treatment, but a few cases develop major depressive disorders. Several predictors of treatment response were identified., (Copyright © 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Objective: Close collaboration between the cancer care team service and the psychiatric consultation service is recommended to provide adequate comprehensive care to cancer patients. In Japan, specialized palliative care teams work in conjunction with consultation-liaison psychiatrists as an essential members. There are, however, few studies reporting on these services., Methods: We obtained the characteristics, physical and psychiatric symptoms and outcomes of cancer patients by analyzing the database of patients referred to the palliative care team at the National Cancer Center Hospital East, Japan., Results: Among consecutive 2000 referrals, most patients referred to the palliative care team present both physical and psychiatric symptoms. Psychiatric diagnoses were provided for ∼70% of these patients. Consultation-liaison psychiatrists provided medical care to 80% of all the referrals. The main symptoms for psychiatric consultation were delirium (28%), adjustment disorder (18%), major depression (7.6%) and dementia (6.6%)., Conclusions: Psychiatric problems are common in cancer patients of the palliative care team. The palliative care team should assess the psychiatric problems in cancer patients, and the involvement of the consultation-liaison psychiatrists in the palliative care teams may be one of the strategies to establish the psychosocial support for cancer patients in the acute hospital settings.

Objective: The purpose of this study is to identify psychiatric disorders and stress factors experienced by staff members in cancer hospitals who were referred to psychiatric consultation service, and to investigate the association between psychiatric disorders and stress factors., Method: A retrospective descriptive study using clinical practice data on staff members referred to psychiatric consultation service, obtained for 8 years, was conducted at two National Cancer Center Hospitals in Japan. Psychiatric disorders were identified according to DSM-IV. Stress factors were extracted from a chief complaint at the initial visit in medical charts, using a coding approach, and grouped as job stress or personal stress. The frequencies of the stress factors were determined by two coders who were unaware of the categorized procedure. Fisher's exact test was used to determine the association between psychiatric disorders and stress factors., Results: Of 8077 psychiatric consultations, 65 (1%) staff members were referred. The most common psychiatric disorder was adjustment disorder (n = 26, 40%), followed by major depression (n = 17, 26%). Eight stress factors were identified from 76 meaning units and were grouped into five job stresses and three personal stresses. Of the five job stresses, four were most frequently experienced in adjustment disorders, and "failure to adapt to job environmental change" was significantly associated (p = 0.014). Two of the three personal stresses were most frequently experienced in psychiatric disorders other than major depressive disorder and adjustment disorders, and "suffering from mental disease" was significantly associated (p = 0.001)., Significance of Results: We found that very few staff members were provided with psychiatric consultation service. A comprehensive support system for job stress might be needed to prevent adjustment disorders, as those are suggested to be the most common psychiatric disorders among staff members in cancer hospitals.

Objective: Major depression is a well-documented risk factor for suicide, and several gender differences in risk factors for suicide exist in cancer patients as well as in the general population. However, no data is available regarding gender differences in risk factors for suicide among cancer patients with major depression., Methods: We investigated the background differences between cancer patients suffering from major depression with or without suicidal ideation according to gender by analyzing the consultation data obtained for patients referred to the Psychiatry Division., Results: Among the 5431 referred patients, 329 males and 399 females were diagnosed as having major depression; among these patients with major depression, 136 (41%) males and 157 (39%) females also had suicidal ideation. A preliminary analysis showed that physical functioning and an advanced stage were potential factors that interacted significantly with gender differences regarding suicidal ideation. A final logistic regression analysis indicated that poor physical functioning and an advanced stage were significant risk factors among male patients., Conclusions: These preliminary findings suggest that gender differences in important indicators of suicidal ideation exist among cancer patients with major depression; these findings may be useful for developing strategies to prevent suicide among cancer patients., (Copyright 2009 John Wiley & Sons, Ltd.)

Purpose: We investigated the association between incidence of various cancers and four single nucleotide polymorphisms (SNPs), two each in two protein tyrosine phosphatase (PTP) genes, PTPRJ and PTPN13, by a case-control study conducted in Japan., Methods: The study samples comprised 819 cancer-free controls and 569 cancer cases including lung, head and neck, colorectal, and esophageal cancers., Results: Compared with the major homozygotes at the Arg326Gln SNP in PTPRJ, a likely homologue of the mouse SCC1 (susceptible to colon cancer), Arg/Gln or Gln/Gln genotypes exhibited an increased colorectal cancer risk with adjusted odds ratios (aOR) of 1.71 (P = 0.021) and 3.74 (P = 4.14 x 10(-4)), respectively. Increased risks were observed with one or more of the combination genotypes of Gln276Pro and Arg326Gln in PTPRJ for most cancer types (aOR range 10.13-55.08, Bonferroni-corrected P = 0.0454-7.20 x 10(-9)). In the PTPN13, major homozygotes of Ile1522Met showed an increased risk for lung squamous cell carcinomas (aOR 1.86), compared to the heterozygotes. Increased risks were observed with at least one of the combination genotypes of the two SNPs, Ile1522Met and Tyr2081Asp, for all but esophageal cancer examined (aOR 3.36-13.75), compared with double heterozygotes. Moreover, these high risks were seen also when all cancer cases were combined (aOR 1.81-6.84)., Conclusions: PTPRJ and PTPN13 SNPs were found to influence susceptibility to a wide spectrum of cancers. Because allelic frequencies of these SNPs are relatively common in many ethnic groups, these findings are worthy of further study.

Objective: The objective of this study was to explore the performances of several diagnostic criteria items for judging the severity of major depression among cancer patients., Method: Using modern item response theory, we examined the performances of the diagnostic criteria outlined by the DSM-IV and two sets of conceptual diagnostic criteria (the Endicott and the Cavanaugh criteria) in a series of 728 cancer patients who had been diagnosed with major depression using an inclusive approach., Results: While all the DSM-IV diagnostic criteria, including feelings of worthlessness and suicidal ideation, had a low ability for discriminating the severity of depression, two proposed items (not participating in medical care and social withdrawal) appeared to be good markers of moderately severe major depressive disorder among cancer patients. In addition, the items "fearfulness or depressed appearance in face or body posture" and "brooding, self-pity or pessimism" may be good markers for mild major depressive disorders, while the item "cannot be cheered up, doesn't smile, no response to good news or funny situations" may be a good marker for severe major depressive disorder., Conclusions: The findings of the present study suggest that alternative criteria may have utility in diagnosing depression severity in cancer patients.

Because of their unique role in linking the innate and adaptive immune systems, dendritic cells (DCs) have been a logical focus for novel immunotherapies. However, strategies employing active immunization with ex vivo generated and antigen-pulsed DCs have shown limited efficacy in clinical trials. These past approaches did not take into account the complex interactions between cells of the innate immune system and DCs during DC maturation, antigen processing, and presentation to naïve T cells. By better understanding the natural sequence of events occurring in vivo during an effective immune response, we can tailor antitumor immunotherapeutic strategies to augment aspects of this response from the activation of innate immune cells to antigen uptake and DC maturation to priming of naïve T cells and, ultimately, to the establishment of antitumor immunity. Current DC vaccination strategies utilize a number of methods to recapitulate the cascade of events that culminate in a protective antitumor immune response.

The significance of L-type amino acid transporter (LAT) 1 expression remains unclear in the metastatic process of human neoplasms, whereas experimental studies have demonstrated that LAT1 is associated with the metastatic process of cancer cells. We compared the immunohistochemical expression of LAT1 and CD98 between the primary site and a concordant pulmonary metastatic site in 93 cancer patients, all of whom had undergone thoracotomy. LAT1, CD98, Ki-67 labeling index, vascular endothelial growth factor (VEGF), CD31, and CD34 were analyzed by immunohistochemical staining in the resected tumors of 93 cancer patients: 45 colon cancers; nine breast cancers; eight head and neck cancers; 11 genital cancers; 14 soft-tissue sarcomas; and six other cancers. The expression of these markers was significantly higher in the metastatic sites than in the primary sites. In total, the positive rates of LAT1, CD98, Ki-67, VEGF, CD31, and CD34 were 40, 24, 56, 41, 45, and 39%, respectively, in the primary sites and 65, 45, 84, 67, 73, and 61%, respectively, in the metastatic sites. LAT1 expression was closely correlated with CD98 expression, angiogenesis, and cell proliferation. The association between LAT1 and CD98 expression was strongest in the primary and metastatic sites. The present study suggests that overexpression of LAT1 and CD98 has an important role to play in the metastatic process of variable human neoplasms. Moreover, LAT1 expression was significantly correlated with cell proliferation and angiogenesis.

Small interfering RNA (siRNA), which induces sequence-dependent gene silencing, has been widely studied. We previously developed polycation liposomes (PCL) as carriers of plasmid DNA and succeeded in showing their potent gene expression efficiency. In the present study, we optimized PCL for siRNA transfection and used it to determine the role of Argonaute2 (Ago2), a main constitution protein of RNA-induced silencing complex (RISC), on angiogenesis. We determined the biological effect of Ago2 knockdown on the angiogenic potential of endothelial cells. Human umbilical vein endothelial cells (HUVECs) stimulated with cytokines including vascular endothelial growth factor (VEGF) were used as an in vitro angiogenesis model. Our data showed that Ago2 knockdown using polycation liposomal Ago2-siRNA (siAgo2) suppressed indispensable processes of angiogenesis, namely endothelial cell proliferation and tube formation. Furthermore, TUNEL staining indicated that the treatment with siAgo2 increased apoptotic cells in comparison to that with control siRNA. These results might be caused by disorder of microRNA system. Next, we attempted to construct systemic siRNA delivery system targeting to angiogenic vessels. Synthetic siRNA was incorporated in polycation liposomes modified with polyethyleneglycol (PEG) and the functional peptide on their surface. Peptide-modified liposomes enhanced cellular uptake of siRNA in comparison with non-modified liposomes. Thus APRPG-modified liposomal siAgo2 may be useful for tumor treatment.

Objective: Psychological distress of cancer patients' family members is treated by psychiatric consultation service for outpatients at National Cancer Center Hospitals in Japan. The purpose of this study was to identify psychiatric disorders and explore background characteristics of cancer patients' family members referred to psychiatric consultation service, so that we could better understand current utilization of this psychiatric consultation service for cancer patients' family members., Methods: A retrospective descriptive study using clinical practice data obtained for 5 years (from January 2000 to December 2004) was conducted at two National Cancer Center Hospitals. We reviewed the psychiatric consultation database, computerized patient database of the National Cancer Center Hospitals, and medical charts of cancer patients' family members who were referred to psychiatry and their cancer patients., Results: Out of a total of 4992 psychiatric consultations, 118 (2%) were for cancer patients' family members. The most common psychiatric disorders among cancer patients' family members were adjustment disorders (n = 69, 58%), followed by major depression (n = 30, 25%). Female (n = 101, 86%), spouse (n = 87, 74%), married (n = 92, 78%), and housewife (n = 63, 53%) were the most common background characteristics of the family members. Sixty-four percent of cancer patients (n = 75) were hospitalized at the time of their family members' referral and 34% of cancer patients (n = 40) had already received psychiatric consultation service and 55% of cancer patients (n = 65) had delivered bad news prior to their family members' referral., Significance of the Research: We found that very few family members were provided with psychiatric consultation service at two National Cancer Center Hospitals. Adjustment disorders are suggested to be the most common psychiatric disorders among cancer patients' family members.

Objective: We previously reported that the nurse-assisted screening and psychiatric referral program (NASPRP) facilitated the psychiatric treatment of depressive patients, but the high refusal rate was a problem even though referral was recommended by the nurse to all positively screened patients. We modified the program so that the nurses could judge the final eligibility of referral using the result of the screening. This study assessed if the modified NASPRP led to more psychiatric referral of depressive patients., Method: We retrospectively evaluated the annual change of the psychiatric referral proportion and compared the findings among the usual care term, the NASPRP term, and the modified NASPRP terms., Results: The referral proportions of the modified NASPRP terms were 4.4% and 3.9%. These were not significantly higher than the usual care term (2.5%), and significantly lower than the NASPRP term (11.5%). SIGNIFICANT OF RESULTS: The modified NASPRP did not facilitate psychiatric treatment of depressive patients and another approach is needed.

The objective of this study was to describe the applicability and the dropout of the pharmacological treatment algorithm for major depressive disorder in patients with advanced cancer. Psychiatrists treated major depressive disorder in advanced cancer patients on the basis of the algorithm. For discussing the problems related to the algorithm, we reviewed the reasons for the non-application of the algorithm and the reasons for dropout of patients within a week of initiation of treatment. The algorithm was applied in 54 of 59 cases (applicability rate, 92%). The reasons for the non-application of the algorithm were as follows: the need to add a benzodiazepine to an antidepressant in 4 cases and the need to choose alprazolam despite the depression being moderate in severity, in order to obtain a rapid onset action and reduce anxiety in a patient with short prognosis. Nineteen of the 55 patients dropped out within a week of initiation of treatment based on the algorithm. Delirium was the most frequent reason for dropout. The applicability rate was high, but several problems were identified, including those related to the combination of antidepressants and benzodiazepines, pharmacological treatment of depression in patients with short prognosis, and delirium due to antidepressants.

The observation that the glycolipid alpha-galactosylceramide (alpha-GalCer) is a potent stimulator of natural killer T (NKT) cells has provided an important means for investigating NKT cell biology. alpha-GalCer is presented on CD1d to the invariant NKT receptor, leading to interleukin-12 (IL-12) production by dendritic cells (DCs) and to NK cell activation. We review our research on the tumor-protective properties of alpha-GalCer, particularly the major role played by DCs. We compared administration of alpha-GalCer on mature DCs with soluble glycolipid and found that DCs induced more prolonged interferon-gamma (IFN-gamma) production by NKT cells and better protection against B16 melanoma. Human alpha-GalCer-loaded DCs also expanded NKT cell numbers in cancer patients. alpha-GalCer-activated NKT cells were then found to induce DC maturation in vivo. The maturing DCs produced IL-12, upregulated co-stimulatory molecules, and induced adaptive immunity to captured cellular antigens, including prolonged, combined CD4(+)/CD8(+) T-cell immunity to dying tumor cells. Surprisingly, co-stimulator-poor tumor cells, if directly loaded with alpha-GalCer ('tumor/Gal') and injected intravenously, also induced strong NKT- and NK-cell responses. The latter killed the tumor/Gal, which were subsequently cross presented by CD1d on DCs to elicit DC maturation and prolonged adaptive T-cell immunity, which lasted 6-12 months. These findings help explain tumor protection via alpha-GalCer and urge development of the DC-NKT axis to provide innate and adaptive immunity to human cancers.