Isamu Adachi

Activation of Intestinal Mucosal Immunity in Tumor‐bearing Mice by Lactoferrin

We have previously demonstrated that oral administration of bovine lactoferrin (bLF) markedly increases CD4+ and CD8+ T cells and NK (asialoGM1+) cells in the blood of tumor‐bearing mice and enhances anti‐metastatic activity. In this paper, we document that oral administration of bLF and bLF‐hydrolysate (bLFH) is associated with strong increases in CD4+ and CD8+ T, as well as asialoGM1+ cells in lymphoid tissues and lamina propria of the small intestine in mice, especially in tumor‐bearing animals in which Co26Lu cells were implanted subcutaneously. Moreover, IgM+ and IgA+ B cells in lamina propria of the small intestine were also significantly increased by bLF and bLFH. Bovine apo‐transferrin (bTF) did not exhibit such activity. In the colon, only CD8+ cells were significantly increased by treatment with bLF, while asialoGM1+ cells were significantly decreased. bLF and bLFH induced cytokines to activate T, B and asialoGM1+ cells. Administration of bLF and bLFH, but not bTF, increased production of interleukin‐18 (IL‐18), interferon‐gamma (IFN‐γ) and caspase‐1 in the mucosa of the small intestine. Particularly high levels of IL‐18 were found in the epithelial cells of the small intestine. Moreover, administration of bLF and bLFH, but not bTF, induced IFN‐γ presenting cells in the small intestine. Caspase‐1, which processes proIL‐18 to mature IL‐18, was also induced in the epithelial cells of the small intestine following treatment with bLF and bLFH, but not with bTF. These results suggest that enhanced production of IL‐18 and IFN‐γ and caspase‐1 induction by treatment with bLF may be important for elevation of intestinal mucosal immunity.

Construction and validation of a practical prognostic index for patients with metastatic breast cancer.

PURPOSE To identify the readily available prognostic factors most helpful in predicting survival and to construct and validate a prognostic index for metastatic breast cancer (MBC) patients. PATIENTS AND METHODS Data from 233 MBC patients, accrued on a multiinstitutional randomized phase III trial (Japan Clinical Oncology Group [JCOG] study 8808), were analyzed to identify significant prognostic factors and a prognostic index was constructed by incorporating these prognostic factors. For validation of the prognostic index, another data set from 315 consecutive MBC patients, who had been treated with standard anthracycline-containing regimens, was analyzed. RESULTS In multivariate regression analyses, history of adjuvant chemotherapy (ADJCT) (P = .0005), presence of distant lymph nodes (DLNs) (P = .0117) and liver (HEP) (P = .0099) metastases, elevation of serum lactate dehydrogenase (LDH) (P < .0001), and shorter disease-free interval (DFI) (P < .0001) significantly contributed to poorer survival. The prognostic index was constructed as follows: Prognostic Index = ADJCT (not received = 0, received = 1) + DLNs (absent = 0, present = 1) + HEP (absent = 0, present = 1) + LDH (< or = one times normal = 0, > one times normal = 1) + DFI (> or = 24 months = 0, < 24 months = 2). With this prognostic index, patients could be stratified into three risk groups. The median survival times (MSTs) of low-, intermediate- and high-risk groups were 45.5, 24.6, and 10.6 months, respectively (P < .0001). This prognostic index was applied to the validation patients. The respective MSTs for each risk group were 49.6,22.8, and 10.0 months (P < .0001). CONCLUSION ADJCT, DLNs, HEP, LDH, and DFI were important prognostic factors for MBC patients. The prognostic index readily enables MBC patients to be stratified into three risk groups and is worth considering for future clinical trials.

Patients' understanding of their own disease and survival potential in patients with metastatic breast cancer.

Purpose: To investigate the effect of understanding their own disease by patients with metastatic breast cancer on their survival potential after being informed by their physician.Patientsandmethods: Two hundred and fourteen women with metastatic breast cancer who participated in a multi-institutional, randomized phase III trial (Japan Clinical Oncology Group (JCOG) Study 8808) were asked whether they understood their own disease after being given information about the clinical trial. They were classified into two groups on the basis of whether they understood or not. We estimated their survival after the time of registration and derived relative hazard ratios from Coxs proportional hazards model.Results: There were 190 patients in the ‘better understanding’ group and 24 in the ‘poor understanding’ group. Median survival times after registration were 28.3 and 16.1 months, respectively. The ‘better understanding’ group showed a significant difference from the ‘poor understanding’ group (p=0.016). In multivariate regression analysis, patients who did not understand still showed poorer survival than those who understood (hazard ratio = 2.09; 95% confidence interval (CI) 1.16–3.78; p=0.014)

Attitudes of Japanese Physicians Toward Terminal Dehydration: A Nationwide Survey

PURPOSE To clarify physician attitudes toward terminal dehydration and identify the physician-related factors contributing to their attitudes. METHODS A cross-sectional survey of Japanese physicians with a self-reported questionnaire was used. RESULTS A total of 584 responses were analyzed (response rate, 53%). In the vignette of a gastric cancer patient with an estimated survival of 1 month and almost impossible oral intake due to intestinal obstruction, 50% chose intravenous hydration of 1,000 mL/d, while 24% selected more than 1,500 mL/d. For a lung cancer patient with cachexia, 58% chose 1,000 mL/d, while 26% selected no hydration or 500 mL. Multivariate analyses revealed that the physicians with more positive attitudes toward intravenous hydration were significantly less involved in end-of-life care, more likely to regard the physiologic requirement of fluid and nutrition as important in initiating intravenous hydration, more likely to believe that intravenous hydration is effective for symptom palliation, and more likely to believe that intravenous hydration is the minimum standard of care. CONCLUSION Physicians have considerably divergent attitudes toward intravenous hydration for terminally ill cancer patients. To resolve the discrepancy, the priority in hydration research should be to clarify the appropriate physiologic requirements of fluid and nutrition in dying patients, the effects of intravenous hydration on patient symptoms, and the reasons why physicians consider intravenous hydration to be the minimum standard of care.

Concerns of family members of patients receiving palliative sedation therapy

PurposeSymptomatic sedation is often required in terminally ill cancer patients and could cause significant distress to their families. The aim of this study was to gather vivid family descriptions about their experiences in palliative sedation therapy.MethodsThis report is an additional analysis of a multicenter questionnaire survey. We performed content analysis on 48 statements described by 185 bereaved family members of patients who received palliative sedation therapy.ResultsFamily members reported guilt, helplessness, and physical and emotional exhaustion when patients received palliative sedation therapy. They were concerned about whether sedated patients experienced distress, wished to know that the maximum efforts had been made, wished to prepare for patient death, wished to tell important things to patients before sedation, wished to understand patients’ suffering, and wanted medical professionals to treat patients with dignity.ConclusionsTo alleviate family distress, clinicians should understand families’ emotional distress, ensure that unconscious patients feel no distress, reassure family members that the symptoms are truly refractory despite maximum efforts for symptom relief, give information and coordinate the situation to enable families to prepare for patient death and to tell important things to patients before sedation, help families to share patients’ suffering, and treat patients the same as when they remained conscious.

Efficacy of Docetaxel 60 mg/m2 in Patients With Metastatic Breast Cancer According to the Status of Anthracycline Resistance

PURPOSE To evaluate the efficacy of docetaxel 60 mg/m2 in metastatic breast cancer (MBC) according to the status of anthracycline resistance. PATIENTS AND METHODS Ninety-nine patients with anthracycline-resistant MBC were treated with docetaxel 60 mg/m2 intravenously for a 90-minute period every 3 to 4 weeks. Anthracycline resistance was defined as primary and secondary resistance. Primary resistance was defined as progression during or within 6 months after completion of adjuvant anthracycline, and no MBC response to a first-line regimen that contained anthracycline. Secondary resistance was defined as progression after a documented clinical response to a first-line anthracycline treatment for MBC. Secondary resistance was further divided into three categories: (1) absolute resistance, or progression during treatment with anthracycline after a period of response; (2) relative resistance, or progression within 6 months after anthracycline administration ended; and (3) sensitive regrowth, or progression more than 6 months after the conclusion of anthracycline administration. RESULTS The response rate in the 99 patients was 35.4% (95% confidence interval, 30.1% to 44.8%). The response rates according to the status of anthracycline resistance were as follows: primary resistance (n = 46), 19.6%; secondary resistance (n = 53), 49.1% (absolute resistance [n = 16], 56.3%); relative resistance (n = 17), 47.1%; and sensitive regrowth (n = 20), 45.0%. The median time to treatment failure in patients with primary resistance was 2.9 months, compared with 5.2 months in patients with secondary resistance (P = .0022). CONCLUSION Docetaxel at a dose of 60 mg/m2 seemed to be effective in MBC with secondary resistance to anthracycline. The status of anthracycline resistance is important for the prediction of response to second-line treatment with docetaxel.

Development of a Predicting Tool for Survival of Terminally Ill Cancer Patients

OBJECTIVE To develop a predicting tool for survival of terminally ill cancer patients. METHODS This prospective, multicenter study was composed of two cohorts of samples: development and test. In the development sample of terminally ill cancer patients, 32 candidate predictors were studied to develop a new tool, Japan Palliative Oncology Study-Prognostic Index using the Cox proportional hazard model. Then the test sample was studied to validate Japan Palliative Oncology Study-Prognostic Index and compared it with the conventional predicting tools, such as palliative prognostic score and simplified palliative prognostic index. RESULTS Five significant predictors, physicians clinical prediction of survival, consciousness, pleural effusion, white blood cell count and lymphocyte % were derived from the analysis of 201 patients, and Japan Palliative Oncology Study-Prognostic Index was developed using these predictors. It could divide patients into three risk groups: low (A), intermediate (B) and high (C). Median survival times for Groups A, B and C were 51, 35 and 16 days, respectively. Survival probability for more than 30 days for Groups A, B and C in the development sample was 78%, 61% and 16%, respectively. Japan Palliative Oncology Study-Prognostic Index was studied in subsequent 208 patients for the test sample, and constant results (median survival times for Groups A, B and C; 67, 31 and 10 days, and survival probability for more than 30 days for Groups A, B and C; 81, 48 and 11%) were obtained. Palliative prognostic score can also predict three risk groups well, but simplified palliative prognostic index could not discriminate low risk from intermediate risk group. CONCLUSION Japan Palliative Oncology Study-Prognostic Index, a tool to predict survival, has been developed. Its reliability should be confirmed further in the future study, comparing with palliative prognostic score.

Physician and Nurse Attitudes Toward Artificial Hydration for Terminally Ill Cancer Patients in Japan: Results of 2 Nationwide Surveys

This study investigated physician and nurse attitudes toward artificial hydration in terminally ill cancer patients and compared differences in attitudes between these 2 professions and among clinical settings in Japan. The response rate was 53% (584/1123) for physicians and 79% for nurses (3328/4210). More physicians answered that artificial hydration alleviates the sensation of thirst. More palliative care unit physicians and nurses answered that withholding artificial hydration alleviated several physical symptoms. Oncologists answered that artificial hydration alleviated the sensation of thirst and fatigue. Discussion among patient-centered teams and individualized decision making are important. Because the differences identified here are attributable to differences in knowledge of artificial hydration for terminal cancer patients, oncologists should place greater emphasis on the opinion of palliative care specialists. Medical practitioners caring for terminal cancer patients should consider a broader range of views on hydration therapy, with a focus on effective hydration techniques and alternative interventions.

Nitric Oxide Synthase in Rat Nasal Mucosa; Immunohistochemical and Histochemical Localization

The localization of nitric oxide synthase (NOS) and its cofactor, nicotinamide-adenine dinucleotide hydrogen phosphate (NADPH)-diaphorase, was examined in the nasal mucosa of the rat by immunohistochemical and histochemical methods. In addition to cryostat sections, whole mount preparations were used to examine the distribution of nerves. Both in the nasal mucosa and in associated ganglia, the distribution of NOS-immunoreactive nervous structures essentially corresponded to that of NADPH-diaphorase-positive ones. The NOS-immunopositive nerve fibers in the respiratory area of the nasal mucosa were distributed around blood vessels and in submucosal glands. Part of the respiratory area was supplied with intraepithelial arborizations of the immunopositive fibers. The epithelial cells in the respiratory area were NADPH-diaphorase positive but NOS immunoreactivity negative. In the olfactory area, the NADPH-diaphorase- and NOS-positive nerve fibers were restricted to blood vessels located deep in the submucosa. Throughout the nasal mucosa, arterial endothelium was NADPH-diaphorase positive but NOS immunoreactivity negative. Both NOS immunoreactivity and NADPH-diaphorase activity were found in major populations of neuronal somata in the sphenopalatine ganglion. The present study provides the direct evidence supporting the notion that nitric oxide is richly produced in autonomic nerves of the nasal mucosa derived from the sphenopalatine ganglion.

Endocrinological evaluations of brief hand massages in palliative care.

BACKGROUND AND OBJECTIVES Some patients with advanced cancer make use of complementary therapies for the reduction of anxiety and stress. These patients can suffer distressing end-of-life symptoms, which conventional treatments might not relieve satisfactorily. Although previous studies have suggested that complementary therapies could be useful for reducing distress in patients with cancer, it has remained unclear whether these benefits are applicable at the end-of-life stage. The current study examined to validate salivary chromogranin A (CgA) as a biomarker for relieving stress by hand massage in terminally ill patients. METHODS The study group comprised 34 inpatients in palliative care units. Each of these patients received a 5-minute massage to the upper extremity. Before and after the massage, saliva samples were collected in order to measure the CgA levels. RESULTS The brief hand massage appears to reduce levels of stress according to the salivary CgA (p < 0.05). In addition, we found statistically significant changes in patient satisfaction with hand massage. CONCLUSIONS Salivary CgA could potentially be used as a biomarker to measure relieving stress by hand massage in a palliative-care setting.