Long-term influence of adjuvant breast radiotherapy on cognitive function in breast cancer patients treated with conservation therapy.

BACKGROUND: The mechanisms underlying cognitive decline after radiotherapy not directed at brain areas remains unclear. We previously suggested that adjuvant breast radiotherapy in breast conservation therapy could lower memory function soon after therapy, and that the process might be partially mediated by plasma interleukin (IL)-6 levels. The present study investigated how that relationship changes longitudinally. METHODS: We performed the Wechsler Memory Scale-Revised (WMS-R) test and measured plasma IL-6 levels for 47 breast cancer surgical patients within 1 year after the initial therapy (study 1) and more than 2 years after study 1 (study 2). We also performed 2 × 2 mixed [the radiotherapy group (n = 25) or the no-radiotherapy group (n = 22) × study 1 or study 2] analysis of covariance on the WMS-R indices and plasma IL-6 levels. The association between changes in plasma IL-6 levels and changes in the WMS-R indices between the two studies was evaluated using Pearson's correlation coefficient. RESULTS: The Immediate Verbal Memory Index was significantly higher in study 2. The Delayed Recall Index was significantly higher in study 2 and significantly lower in the radiotherapy group only in study 1. There was a significant correlation between changes in plasma IL-6 levels and changes only in the Delayed Recall Index of the WMS-R. CONCLUSIONS: Memory decline in breast cancer patients soon after adjuvant breast radiotherapy was restored approximately 3 years after treatment, and decreased plasma IL-6 levels might be involved in the recovery process.

Association between adjuvant regional radiotherapy and cognitive function in breast cancer patients treated with conservation therapy.

Although protracted cognitive impairment has been reported to occur after radiotherapy even when such therapy is not directed to brain areas, the mechanism remains unclear. This study investigated whether breast cancer patients exposed to local radiotherapy showed lower cognitive function mediated by higher plasma interleukin (IL)-6 levels than those unexposed. We performed the Wechsler Memory Scale-Revised (WMS-R) and measured plasma IL-6 levels for 105 breast cancer surgical patients within 1 year after the initial therapy. The group differences in each of the indices of WMS-R were investigated between cancer patients exposed to adjuvant regional radiotherapy (n = 51) and those unexposed (n = 54) using analysis of covariance. We further investigated a mediation effect by plasma IL-6 levels on the relationship between radiotherapy and the indices of WMS-R using the bootstrapping method. The radiotherapy group showed significantly lower Immediate Verbal Memory Index and Delayed Recall Index (P = 0.001, P = 0.008, respectively). Radiotherapy exerted an indirect effect on the lower Delayed Recall Index of WMS-R through elevation of plasma IL-6 levels (bootstrap 95% confidence interval = -2.6626 to -0.0402). This study showed that breast cancer patients exposed to adjuvant regional radiotherapy in conservation therapy might have cognitive impairment even several months after their treatment. The relationship between the therapy and the cognitive impairment could be partially mediated by elevation of plasma IL-6 levels.

Associations of interleukin-6 with vegetative but not affective depressive symptoms in terminally ill cancer patients.

PURPOSE: Previous studies have reported associations of depressive symptoms with pro-inflammatory cytokines, especially with interleukin-6 (IL-6) in noncancer subjects and cancer patients. Meanwhile, symptoms such as tiredness and appetite loss may be vegetative symptoms of depression when associated with other diagnostic criteria of depression. Such vegetative-type symptoms worsen during the last 6 months of life in cancer patients and may not be associated with affective depressive symptoms such as sadness and nervousness. This study explored associations between depressive symptoms and plasma IL-6 in terminally ill cancer patients whose survival period was confirmed to be less than 6 months by follow-up, with attention to differences in vegetative and affective depressive symptoms. METHODS: Data from 112 consecutively recruited terminally ill cancer patients who registered at a palliative care unit without any active anticancer treatment were used. Plasma IL-6 levels were measured using an electrochemiluminescence assay. Depressive symptoms included in the DSM-IV and Cavanaugh criteria were assessed by structured interviews and were categorized into affective symptoms and vegetative symptoms. Affective symptoms were also measured with the depression subscale of the Hospital Anxiety and Depression Scale, which does not include vegetative symptoms. RESULTS: Vegetative symptoms, such as appetite loss, insomnia, and fatigue, were significantly associated with IL-6 levels. However, neither of the affective symptoms nor their severity was associated with IL-6 levels. CONCLUSIONS: IL-6 was associated with vegetative depressive symptoms in terminally ill cancer patients but not with affective depressive symptoms, suggesting possible differences in the pathophysiological mechanisms between these sets of symptoms.

R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling.

In mammals, female development has traditionally been considered a default process in the absence of the testis-determining gene, Sry. Recently, it has been documented that the gene for R-spondin1 (RSPO1), a novel class of soluble activator for Wnt/beta-catenin signaling, is mutated in two Italian families with female-to-male (XX) sex reversal. To elucidate the role of Rspo1 as a candidate female-determining gene in a mouse model, we generated Rspo1-null (Rspo1(-/-)) mice and found that Rspo1(-/-) XX mice displayed masculinized features including pseudohermaphroditism in genital ducts, depletion of fetal oocytes, male-specific coelomic vessel formation and ectopic testosterone production in the ovaries. Thus, although Rspo1 is required to fully suppress the male differentiation program and to maintain germ cell survival during the development of XX gonads, the loss of its activity has proved to be insufficient to cause complete XX sex reversal in mice. Interestingly, these partial sex-reversed phenotypes of Rspo1(-/-) XX mice recapitulated those of previously described Wnt-4(-/-) XX mice. In accordance with this finding, the expression of Wnt-4 and its downstream genes was deregulated in early Rspo1(-/-) XX gonads, suggesting that Rspo1 may participate in suppressing the male pathway in the absence of Sry and maintaining oocyte survival through positively regulating Wnt-4 signaling.

Plasma interleukin-6 and fatigue in terminally ill cancer patients.

Fatigue is one of the most distressing symptoms among terminally ill cancer patients. However, no effective intervention has been established. Several studies have suggested the role of cytokines in fatigue in cancer patients receiving anti-cancer treatment, patients with metastatic cancer, and cancer survivors, but not in terminally ill cancer patients. In the present study, the potential association between fatigue and plasma interleukin-6 (IL-6) was examined in 46 terminally ill cancer patients (median survival: 64.5 days) who received neither steroids nor nonsteroidal anti-inflammatory drugs. Fatigue was evaluated by the Cancer Fatigue Scale (CFS), which consists of multiple dimensions of fatigue, such as Physical, Affective, and Cognitive subscales. Plasma IL-6 levels were measured using an enzyme-linked immunosorbent assay and were compared between patients with and without "clinical fatigue" as defined by the total score of the CFS. Additionally, associations between each of the CFS scores and IL-6 levels were examined. As a result, the IL-6 level in patients with clinical fatigue (n=27 [59%]; mean, SD, median, and range: 37.1, 46.4, 17.1, and 3.7-182.5pg/ml, respectively) was significantly higher than those without clinical fatigue (n=19 [41%]; mean, SD, median, range: 14.3, 12.2, 8.0, and 2.8-45.0pg/ml, respectively) (P=0.02). The IL-6 level significantly correlated with the Physical subscale score (r=0.35, P=0.02), but not with other subscale scores. In conclusion, IL-6 may play a role in fatigue, especially in the physical dimension, in terminally ill cancer patients. The results of the present study provide information to develop a new treatment strategy for cancer fatigue in terminally ill cancer patients.

Burnout and psychiatric morbidity among physicians engaged in end-of-life care for cancer patients: a cross-sectional nationwide survey in Japan.

PURPOSE: To determine the prevalence of burnout and psychiatric morbidity among physicians engaged in end-of-life care for cancer patients in Japan and to explore associated factors related to end-of-life care. METHODS: Questionnaires were mailed to 1436 Japanese clinical oncologists and palliative care physicians with a request to complete the Maslach Burnout Inventory (MBI), the General Health Questionnaire (GHQ-12), and to report on individual factors, including confidence in patient care. High levels of burnout and psychiatric morbidity were identified using cut-off scores of the MBI and GHQ-12. RESULTS: A total of 697 physicians returned the questionnaires (response rate, 49.6%). Twenty-two percent of the respondents had a high level of emotional exhaustion, 11% had a high level of depersonalization, 62% had a low level of personal accomplishment, and 20% had psychiatric morbidity. Clinical oncologists showed a significantly higher psychiatric morbidity than palliative care physicians. Confidence in having sufficient time to communicate with patients was significantly associated with all the burnout subscales. CONCLUSIONS: A low level of personal accomplishment was relatively high among Japanese physicians compared with previous studies. Insufficient confidence in the psychological care of patients was associated with physician burnout rather than involvement in end-of-life care.

Regional cerebral glucose metabolism in patients with secondary depressive episodes after fatal pancreatic cancer diagnosis.

BACKGROUND: Secondary depression is common in the clinical oncology setting after pancreatic cancer diagnosis, following which the patients have to face the fact that they have a cancer with an extremely poor prognosis. However, the specific pathophysiology remains unclear. The present study examined the regional cerebral glucose metabolism using F18-fluorodeoxyglucose (F18-FDG) positron emission tomography (PET) in antidepressant-naïve pancreatic cancer patients with a depressive episode after their cancer diagnosis and before their cancer treatment. METHODS: Regional cerebral glucose metabolism in pancreatic cancer patients without any antidepressant medication after the cancer diagnosis was measured with F18-FDG PET. A depressive episode after the cancer diagnosis was defined as including major and minor depressive episodes, and was diagnosed using the Diagnostic and Statistical Manual, Fourth Edition (DSM-IV). The prefrontal and limbic regions were the primary regions-of-interest, and an uncorrected value of p<0.005 was used as significant. RESULTS: Six of 21 pancreatic cancer patients were diagnosed as having a depressive episode. Significantly higher glucose metabolism in depressed patients was found in the subgenual anterior cingulate cortex (sACC) (uncorrected p=0.002). LIMITATIONS: There was a small number of subjects, and there were no healthy controls. CONCLUSIONS: The higher metabolism in the sACC may be associated with the pathophysiology of secondary depressive episodes in patients following pancreatic cancer diagnosis.

AMSH, an ESCRT-III associated enzyme, deubiquitinates cargo on MVB/late endosomes.

The appropriate sorting of vesicular cargo, including cell-surface proteins, is critical for many cellular functions. Ubiquitinated cargo is targeted to endosomes and digested by lysosomal enzymes. We previously identified AMSH, a deubiquitination enzyme (DUB), to be involved in vesicular transport. Here, we purified an AMSH-binding protein, CHMP3, which is an ESCRT-III subunit. ESCRT-III functions on maturing endosomes, indicating AMSH might also play a role in MVB/late endosomes. Expression of an AMSH mutant lacking CHMP3-binding ability resulted in aberrant endosomes with accumulations of ubiquitinated cargo. Nevertheless, CHMP3-binding capability was not essential for AMSH's in vitro DUB activity or its endosomal localization, suggesting that, in vivo, the deubiquitination of endosomal cargo is CHMP3-dependent. Ubiquitinated cargo also accumulated on endosomes when catalytically inactive AMSH was expressed or AMSH was depleted. These results suggest that both the DUB activity of AMSH and its CHMP3-binding ability are required to clear ubiquitinated cargo from endosomes.

Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy.

BACKGROUND: Previous studies have shown cognitive impairment in breast cancer survivors who were exposed to adjuvant chemotherapy. Neural damage by chemotherapy might have played some part in these findings. The current study explored the regional brain volume difference between breast cancer survivors exposed to adjuvant chemotherapy (C+) and those unexposed (C-). METHODS: High-resolution 1.5-tesla brain magnetic resonance imaging (MRI) databases of breast cancer survivors and healthy controls were used. Brain images were preprocessed for optimal voxel-based morphometry. Comparisons of gray matter and white matter were performed between the C+ and the C- groups, by using MRI scans from within 1 year (the 1-year study, n = 51 and n = 55, respectively) or 3 years after their cancer surgery (the 3-year study, n = 73 and n = 59, respectively). As exploratory analyses, correlation analyses were performed between indices of the Wechsler Memory Scale-Revised and regional brain volume where the volume were significantly smaller. As a reference, MRI scans of cancer survivors were compared with those of healthy controls (n = 55 for the 1-year study and n = 37 for the 3-year study). RESULTS: The C+ patients had smaller gray matter and white matter including prefrontal, parahippocampal, and cingulate gyrus, and precuneus in the 1-year study. However, no difference was observed in the 3-year study. The volumes of the prefrontal, parahippocampal gyrus, and precuneus were significantly correlated with indices of attention/concentration and/or visual memory. Comparisons with healthy controls did not show any significant differences. CONCLUSIONS: Adjuvant chemotherapy might have an influence on brain structure, which may account for previously observed cognitive impairments.

Screening for depression in terminally ill cancer patients in Japan.

This study attempted to assess the performance of several screening instruments for adjustment disorders (ADs) and major depression (MD) among terminally ill Japanese cancer patients. Two hundred and nine consecutive patients were assessed for ADs and MD using a structured clinical interview at the time of their registration with a palliative care unit, and two single-item interviews ("Are you depressed?" and "Have you lost interest?") and the Hospital Anxiety and Depression Scale (HADS) were administered. Screening performance was investigated by calculating sensitivity, specificity, the positive predictive value, negative predictive value, likelihood ratio, and stratum-specific likelihood ratios. When the screening target included both an AD and MD, the HADS is a more useful screening method than the single-item interviews. Regarding screening for MD, both single-item interviews and the HADS possess useful screening performance. Different screening instruments may be recommended depending on the depressive disorders and specific populations.

Biomedical and psychosocial determinants of intrusive recollections in breast cancer survivors.

The authors' aim was to identify the determinants of intrusive recollections related to receiving a cancer diagnosis in women after cancer treatment. A consecutive series of breast cancer patients at 3-15 months after surgery, consisting of subjects with (N=63) and without (N=92) intrusive recollections was examined. Logistic regression analysis revealed that neuroticism, precancer intrusive recollections, and the number of cancer patients in relatives by marriage were final significant determinants, and receiving radiotherapy was an associated factor. These results suggest that biopsychosocial factors contribute to intrusive recollections and have clinical implications for the use of these characteristics in screening and early intervention.

Occurrence of fatigue and associated factors in disease-free breast cancer patients without depression.

GOALS OF WORK: Studies on fatigue in disease-free breast cancer patients have consistently found a significant association between fatigue and depression; and some characteristics of this fatigue may be confused with and/or concealed by those of depression. To clarify the characteristics of fatigue in disease-free breast cancer patients, we examined the frequency of fatigue and associated factors in disease-free breast cancer patients without major depression. PATIENTS AND METHODS: Seventy-nine ambulatory breast cancer patients without major depression who had been disease-free for more than 3 years since their surgery completed the Cancer Fatigue Scale (CFS), a multidimensional scale assessing cancer-related fatigue. Participants also completed the Short-form Eysenck Personality Questionnaire-Revised (EPQR) for assessing their personalities. Sociodemographic, physical, and treatment-related factors were also obtained by interview. MAIN RESULTS: We found that 36.7% of the patients exhibited fatigue and that fatigue was significantly associated with neuroticism. CONCLUSIONS: These results suggest that a considerable number of disease-free breast cancer patients without major depression experience fatigue and that careful attention to those exhibiting high neuroticism may be of benefit in ameliorating their fatigue.

Major depression, adjustment disorders, and post-traumatic stress disorder in terminally ill cancer patients: associated and predictive factors.

PURPOSE: Few studies have been conducted to elucidate the psychological distress of terminally ill cancer patients. This study attempted to determine the prevalence of adjustment disorders (AD), major depression (MD), and post-traumatic stress disorder (PTSD) among terminally ill cancer patients, to identify factors that contribute to them, and to determine how they change longitudinally. PATIENTS AND METHODS: Consecutive terminally ill cancer patients were recruited. Patients were assessed for psychiatric disorders by structured clinical interview twice: once at the time of their registration with a palliative care unit (baseline), and again at the time of their palliative care unit admission (follow-up). Possible contributed biomedical and psychosocial factors were evaluated. RESULTS: The proportions of patients diagnosed with AD, MD, and PTSD at baseline (n = 209) were 16.3%, 6.7%, and 0% respectively, whereas at follow-up (n = 85), 10.6% were diagnosed with AD and 11.8% with MD. Lower performance status, concern about being a burden to others, and lower satisfaction with social support were significantly associated with AD/MD at baseline. There were changes in the diagnosis of AD and MD in 30.6% of the patients. Only the Hospital Anxiety and Depression Scale at the baseline was significantly predictive of AD/MD at follow-up. CONCLUSION: The factors underlying psychological distress are multifactorial. Early intervention to treat subclinical anxiety and depression may prevent subsequent psychological distress.

Suicidality in terminally ill Japanese patients with cancer.

BACKGROUND: The risk of suicide is higher in patients with cancer than in the general population, making end-of-life care of suicidal terminal patients with cancer critical. To identify factors and longitudinal changes associated with suicidality among terminally ill Japanese patients with cancer, a prospective cohort study was performed. METHODS: Consecutive outpatients with cancer who registered with a palliative care unit participated. Structured interviews (e.g., Structured Clinical Interview for DSM- III-R [SCID]) were conducted to assess patient suicidal ideation (Ideation) and interest in requesting euthanasia (Interest) as main outcome measures of suicidality. Possible correlated factors also were investigated. The authors analyzed the data from 140 terminally ill patients with cancer at initial study participation (baseline) whose subsequent survival time was < 6 months. Of these 140 patients, 57 (40.7%) completed the follow-up assessment after admission to the unit. RESULTS: At baseline, 8.6% of the patients had Ideation and 5.0% had Interest. Self-reported anxiety and depression was significantly associated with Ideation (P= 0.003). Changes in Ideation and Interest occurred in 38.6% and 15.8% of the patients, respectively. Ideation was more likely to change than Interest (P = 0.006). The current study did not identify factors that predict changes and occurrences of suicidal ideation and interest in requesting euthanasia. CONCLUSIONS: Suicidality can change even in terminally ill patients. End-of-life care that focuses on the psychologic distress of dying individuals may be a way of preventing suicide.

Cancer-related intrusive thoughts as an indicator of poor psychological adjustment at 3 or more years after breast surgery: a preliminary study.

Intrusive thoughts are one of the re-experiencing symptoms in posttraumatic stress disorder, and have been suggested as a predictor for the continuous presence of psychological distress in cancer survivors. The aim of this preliminary study was to examine the possibility of using cancer-related intrusive thoughts (CITs) as an indicator of psychological distress and adjustment after breast surgery. A consecutive series of ambulatory breast cancer survivors at 3 or more years after surgery were given the Structured Clinical Interview for DSM-IV (SCID) and self-report questionnaires, including Profile Of Mood States (POMS), Impact of Event Scale (IES) and Mental Adjustment to Cancer (MAC) scale, to measure psychological distress and/or adjustment. The SCID identified a history of CITs in 34 (46%) of the 74 participants. No significant differences were found in the POMS and IES psychological distress scores between subjects with and without a history of CITs. Subjects with a history of CITs showed significantly higher levels of anxious preoccupation, one of the MAC subscale scores. The association continued to be significant after controlling for potential confounders such as social support, depression, avoidance, arousal, and neuroticism. The results indicated that CITs might be useful for indicating poor psychological adjustment, but not distress, in patients at 3 or more years after breast surgery.

Practices and attitudes of Japanese oncologists and palliative care physicians concerning terminal sedation: a nationwide survey.

PURPOSE: To clarify the frequency of practice of sedation therapy for terminally ill cancer patients and to identify physicians' attitudes toward sedation. METHODS: Questionnaires were mailed to 1,436 Japanese oncologists and palliative care physicians with a request to report their practice of and attitudes toward palliative sedation therapy. RESULTS: A total of 697 physicians returned questionnaires (response rate, 49.6%). Use of mild, intermittent-deep, or continuous-deep sedation for physical and psychologic distress was reported by 89% and 64%, 70% and 46%, and 66% and 38%, respectively. In vignettes in which physicians were asked whether they would use sedation for a patient with refractory dyspnea or with existential distress, 14% and 15%, respectively, chose continuous-deep sedation as a strong possibility. Those physicians less confident with psychologic care and with higher levels of professional burnout were more likely to choose continuous-deep sedation. In vignettes in which they were asked whether they use sedation for a patient with depression or delirium, 39% and 31%, respectively, considered psychiatric treatment to be a strong possibility, and 42% and 50% regarded continuous-deep sedation as a potential treatment option. Physicians less involved in caring for the terminally ill and less specialized in palliative medicine were significantly less likely to choose psychiatric treatment. CONCLUSION: Sedation is frequently used for severe physical and psychologic distress of cancer patients. Physicians' clinical experiences with the terminally ill and their levels of professional burnout influence the decisions. Training and education for physicians in regard to end-of-life care and valid clinical guidelines for palliative sedation therapy are necessary.