Value of religious care for relief of psycho‐existential suffering in Japanese terminally ill cancer patients: the perspective of bereaved family members

Objective: This study aimed to clarify the experience of bereaved family members of cancer patients regarding the usefulness of religious care (perceived usefulness). The value of this care to palliate psycho‐existential suffering in future patients was also examined (predicted usefulness). Methods: A questionnaire was sent to 592 bereaved family members of cancer patients who were admitted to certified palliative care units in Japan. Responses were obtained from 378 families, indicating whether the patient received religious care, the perceived usefulness of the care, and its predicted usefulness for palliation of psycho‐existential suffering. Results: About 25% (N=83) indicated that the patient had received religious care, whereas 75% (N=255) had not received it. Families of patients who had received religious care evaluated pastoral care workers (86%), religious services (82%), and religious music (80%) as ‘very useful’ or ‘useful’. Families predicted usefulness of religious care for future patients: attending a religious service (very useful or useful, 56%; not useful or harmful, 44%), a religious atmosphere (48%, 52%), meeting with a pastoral care worker (50%, 50%), and religious care by physicians (26%, 74%), and nurses (27%, 73%). Families with a religion were significantly more likely to rate religious care as useful for future patients. Conclusions: Families of patients who received religious care generally evaluated this care to be very useful or useful. For future patients, some families felt that religious care would be useful, but some did not. In Japan, religious care is more likely to provide benefits to patients who have a religion. Copyright © 2009 John Wiley & Sons, Ltd.     

A 4-week versus a 3-week schedule of gemcitabine monotherapy for advanced pancreatic cancer: a randomized phase II study to evaluate toxicity and dose intensity

Background

This randomized phase II study compared the efficacy and toxicity between 4-week and 3-week schedules of gemcitabine monotherapy in advanced pancreatic cancer.

Methods

Patients with advanced pancreatic cancer were randomly assigned to either a 4-week schedule (gemcitabine at 1000?mg/m2 as a 30-min infusion weekly for 3 consecutive weeks every 4?weeks) or a 3-week schedule (gemcitabine at 1000?mg/m2 as a 30-min infusion weekly for 2 consecutive weeks every 3?weeks). The primary endpoint was the compliance rate during the first 8?weeks between the two groups.

Results

A total of 90 patients were enrolled. The compliance rate during the first 8?weeks was the same (53.3%). For the 4- and 3-week schedules, the tumor response rates were 14.2 and 17.1% (p?=?0.92), median progression free survival was 112 and 114?days (p?=?0.82), and median overall survival was 206 and 250?days (p?=?0.84), respectively. Grade 3?? neutropenia was the major adverse event in both schedules: 37.7 and 35.5% (p?=?0.82). In contrast, thrombocytopenia (platelet count <70000/mm3) was significantly higher for the 4-week schedule: 26.6 and 4.4% (p?=?0.008). The mean received dose intensity was equal: 588 and 550?mg/m2/week (p?=?0.14).

Conclusions

The 3-week schedule of gemcitabine did not improve the compliance rate during 8?weeks compared with the 4-week schedule, but it attained a comparable efficacy with lower toxicity. Further investigation will be needed to introduce it into daily practice. Clinical trial registration number: UMIN ID 974.     

Suppression of melanoma growth and metastasis by DNA vaccination using an ultrasound-responsive and mannose-modified gene carrier

DNA vaccination has attracted much attention as a promising therapy for the prevention of metastasis and relapse of malignant tumors, especially highly metastatic tumors such as melanoma. However, it is difficult to achieve a potent cancer vaccine effect by DNA vaccination, since the number of dendritic cells, which are the major targeted cells of DNA vaccination, is very few. Here, we developed a DNA vaccination for metastatic and relapsed melanoma by ultrasound (US)-responsive and antigen presenting cell (APC)-selective gene carriers reported previously, named Man-PEG???? bubble lipoplexes. Following immunization using US exposure and Man-PEG(2000) bubble lipoplexes constructed with pUb-M, which expresses ubiquitylated melanoma-specific antigens (gp100 and TRP-2), the secretion of Th1 cytokines (IFN-γ and TNF-α) and the activities of cytotoxic T lymphocytes (CTLs) were specifically enhanced in the presence of B16BL6 melanoma antigens. Moreover, we succeeded in obtaining potent and sustained DNA vaccine effects against solid and metastatic tumor derived from B16BL6 melanoma specifically. The findings obtained from this study suggest that the gene transfection method using Man-PEG???? bubble lipoplexes and US exposure could be suitable for DNA vaccination aimed at the prevention of metastatic and relapsed cancer.     

Association of WT1 IgG antibody against WT1 peptide with prolonged survival in glioblastoma multiforme patients vaccinated with WT1 peptide

We previously evaluated Wilms’ tumor gene 1 (WT1) peptide vaccination in a large number of patients with leukemia or solid tumors and have reported that HLA‐A*24:02 restricted, 9‐mer WT1‐235 peptide (CYTWNQMNL) vaccine induces cellular immune responses and elicits WT1‐235‐specific cytotoxic T lymphocytes (CTLs). However, whether this vaccine induces humoral immune responses to produce WT1 antibody remains unknown. Thus, we measured IgG antibody levels against the WT1‐235 peptide (WT1‐235 IgG antibody) in patients with glioblastoma multiforme (GBM) receiving the WT1 peptide vaccine. The WT1‐235 IgG antibody, which was undetectable before vaccination, became detectable in 30 (50.8%) of a total of 59 patients during 3 months of WT1 peptide vaccination. The dominant WT1‐235 IgG antibody subclass was Th1‐type, IgG₁ and IgG₃. WT1‐235 IgG antibody production was significantly and positively correlated with both progression‐free survival (PFS) and overall survival (OS). Importantly, the combination of WT1‐235 IgG antibody production and positive delayed type‐hypersensitivity (DTH) to the WT1‐235 peptide was a better prognostic marker for long‐term OS than either parameter alone. These results suggested that WT1‐235 peptide vaccination induces not only WT1‐235‐specific CTLs as previously described but also WT1‐235‐specific humoral immune responses associated with antitumor cellular immune response. Our results indicate that the WT1 IgG antibody against the WT1 peptide may be a useful predictive marker, with better predictive performance in combination with DTH to WT1 peptide, and provide a new insight into the antitumor immune response induction in WT1 peptide vaccine‐treated patients.     

Influence of compression on water sorption, glass transition, and enthalpy relaxation behavior of freeze-dried amorphous sugar matrices

An amorphous matrix comprised of sugar molecules are frequently used in the pharmaceutical industry. The compression of the amorphous sugar matrix improves the handling. Herein, the influence of compression on the water sorption of an amorphous sugar matrix was investigated. Amorphous sugar samples were prepared by freeze-drying, using several types of sugars, and compressed at 0-443 MPa. The compressed amorphous sugar samples as well as uncompressed samples were rehumidified at given RHs, and the equilibrium water content and glass transition temperature (T(g)) were then measured. Compression resulted in a decrease in the equilibrium water content of the matrix, the magnitude of which was more significant for smaller sized sugars. Diffusivity of water vapor in the sample was also decreased to one-hundredth by the compression. The T(g) value for a given RH remained unchanged, irrespective of the compression. Accordingly, the decrease in T(g) with increasing water content increased as the result of compression. The structural relaxation of the amorphous sugar matrices were also examined and found to be accelerated to the level of a non-porous amorphous sugar matrix as the result of the compression. The findings indicate that pores contained in freeze-dried sugar samples interfere with the propagation of structural relaxation.     

Endocrine disrupting effects of low dose 17 β-estradiol (E2) on the Japanese quail (Coturnix japonica) were detected by modified one-generation reproduction study

Previously, we investigated endocrine disrupting effects of 17 β-estradiol (E(2)) on Japanese quail (Coturnix japonica) in the avian reproduction test according to the testing guidelines, in which new endpoints such as blood vitellogenin (VTG) concentration in parent quails and pathology of F(1) chicks were added, and consequently these additional endpoints suggested to be sensitive markers for detecting any impacts of endocrine disrupting effects (Shibuya et al., 2005b). In the present study, to investigate low dose effects of estrogenic endocrine disrupting chemicals in birds, the avian reproduction study of E(2) at low dose levels was conducted using Japanese quail with additional endpoints such as observations of F(1) chicks until 10 weeks of age, histopathology of F(1) chicks at 14 days and 10 weeks of age and blood VTG concentration in parent quails. Sixteen pairs of 10-week-old quails were fed a low phytoestrogen diet containing E(2) at 0 (control), 0.3, 3, and 30 ppm for 6 weeks, and parent quails, eggs and offspring were examined. F(1) chicks were maintained up to 14 days or 10 weeks of age. Serum E(2) and VTG concentrations in males of the E(2) 3- and 30-ppm groups and in females of the E(2) 30-ppm groups were significantly elevated. In the E(2) 30-ppm group, two parent females died, and toxic changes such as suppression of body weight gain, decrease in food consumption and atrophic and degenerative changes of the reproductive organs were observed in parent quails. In the same group, the number of eggs laid and the fertility rate of eggs were significantly decreased. In addition, the viability of F(1) chicks in the E(2) 30-ppm group were significantly decreased at 10 weeks of age. On the other hand, no abnormalities described above were observed in any parent quails, eggs and F(1) chicks in the E(2) 3- and 0.3-ppm groups, although the fertility rates of eggs in both groups were decreased and the body weight gain of F(1) females in the E(2) 3-ppm group was significantly suppressed. In the histopathological examination of F(1) chicks maintained up to 10 weeks of age, persistent right oviduct and atrophy of the oviduct gland were observed in females of E(2)-treatment groups with significantly high incidences. Moreover, cystic dilatation and tubular degeneration of the seminiferous tubules and atrophy of the cloacal gland were also observed in males of the E(2)-treatment groups. Thus, the dietary treatment of low dose E(2) (even 0.3 ppm) to parent quails resulted in decreased viability and induction of abnormalities in the oviduct, testis and cloacal gland in F(1) chicks maintained up to 10 weeks of age. These results suggest that additional endpoints such as observations of F(1) chicks until 10 weeks of age, histopathology of F(1) chicks at 14 days and 10 weeks of age and blood VTG concentration in parent quails would be useful and sensitive endpoints for evaluating estrogenic endocrine disrupting effects in the avian reproduction study.     

The D5Mit7 locus on mouse chromosome 5 provides resistance to gamma-ray-induced but not N-methyl-N-nitrosourea-induced thymic lymphomas

Susceptibility to gamma-ray induction of thymic lymphomas in mouse strains is controlled by low-penetrance genetic variant alleles. Our previous genome-wide scan of a mouse backcross between BALB/c and MSM strains suggested the existence of a BALB/c resistance locus near D5Mit5 on chromosome 5. To confirm this resistance, we produced congenic mice carrying a 28.4 cM region between D5Mit4 and D5Mit315 from the MSM parental strain on the BALB/c background. Lymphomas were induced in their progeny by gamma-ray irradiation or administration of N-methyl-N-nitrosourea (MNU), an alkylating agent. The incidence of radiogenic lymphomas was 87.5% in mice of the M/M genotype at D5Mit7, significantly higher than the 46% incidence in mice of the C/M genotype, indicating highly significant linkage between the locus and the resistance (P = 0.000054). In contrast, the frequencies of MNU-induced thymic lymphomas were similar between the two genotypes (P = 0.35 in chi2 test). These results confirm the presence of a resistance allele for gamma-ray induction of thymic lymphomas near the D5Mit7 locus and strongly suggest that this locus modifies carcinogenic risk from exposure to radiation but not to alkylating agents.     

Impact of serum interleukin-18 level as a prognostic indicator in patients with epithelial ovarian carcinoma

Background Interleukin-18 (IL-18), a cytokine produced by macrophages, is capable of inducing T-lymphocyte synthesis of interferon- (IFN-). In this study, for the first time, the serum concentration of IL-18 and its significance as a prognostic indicator was evaluated in patients with epithelial ovarian cancer.Methods The serum IL-18 level was measured by an enzyme-linked immunosorbent assay (ELISA) in 69 patients with epithelial ovarian cancer and 8 healthy controls. Relationships between the IL-18 level and clinicopathological features were examined by univariate and multivariate analyses.Results The median serum IL-18 level in the ovarian cancer patients was 229.6pg/ml, and the level was significantly elevated compared with that in the normal controls (151.3pg/ml; P 0.01). No significant correlations were detected between the IL-18 level and stage or histology (P = 0.08 and P = 0.12, respectively). On univariate analysis, overall survival was shown to be affected by IL-18 serum levels. However, multivariate analysis failed to demonstrate an independent prognostic significance for IL-18 serum levels, while confirming the role of previously established prognostic variables, such as performance status, stage, and residual tumor.Conclusion This study showed that IL-18 serum levels were elevated in ovarian cancer patients and were correlated with overall survival, although they were shown not to be an independent prognostic factor.     

Matrix metalloproteinase-2 status in stromal fibroblasts, not in tumor cells, is a significant prognostic factor in non-small-cell lung cancer.

PURPOSE: The purpose is to assess clinical significance of matrix metalloproteinase (MMP)-2 and MMP-9 status, especially MMP-2 status, in stromal cells in non-small-cell lung cancer (NSCLC) because experimental studies have revealed that stromal MMP-2 plays important roles in progression of malignant tumors, but most clinical studies focused on tumoral MMP-2 expression, not stromal MMP-2 expression. EXPERIMENTAL DESIGN: We conducted a retrospective study on MMP-2 and MMP-9 expression as evaluated immunohistochemically in a total of 218 consecutive patients with completely resected pathological stage I-IIIA, NSCLC. RESULTS: Strong MMP-2 expression in tumor cells and stromal fibroblasts were documented in 54 (24.8%) and 132 (60.6%) patients, respectively. Strong MMP-2 expression in stromal fibroblasts was more frequently seen in squamous cell carcinoma (72.7%) than in adenocarcinoma (54.9%; P = 0.016). Tumors showing strong MMP-2 expression in stromal fibroblasts showed a significantly higher intratumoral microvessel density (IMVD) than weak stromal MMP-2 tumors (mean intratumoral microvessel density, 50.9 versus 32.4, P = 0.003). In addition, postoperative prognosis of strong stromal MMP-2 patients was significantly poorer than that of weak stromal MMP-2 patients (5-year survival rate, 77.5 versus 60.2%, P = 0.032), and the prognostic significance was enhanced in squamous cell carcinoma patients but disappeared in adenocarcinoma patients. Multivariate analyses confirmed that strong stromal MMP-2 expression was a significant factor to predict a poor prognosis in squamous cell carcinoma patients, not in adenocarcinoma patients. In contrast, MMP-2 or MMP-9 status in tumor cells was not a significant prognostic factor. CONCLUSIONS: MMP-2 status in stromal fibroblasts, not in tumor cells, was a significant prognostic factor associated with angiogenesis in NSCLC.