Oxaliplatin-based adjuvant chemotherapy duration (3 versus 6 months) for high-risk stage II colon cancer: the randomized phase III ACHIEVE-2 trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy may be associated with debilitating peripheral sensory neuropathy (PSN) in patients with high-risk stage II colon cancer. This open-label, multicenter, randomized phase III trial was conducted as a prospective pooled analysis to investigate the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy. PATIENTS AND METHODS: From 12 February 2014 to 31 January 2017, 525 Asian patients with high-risk stage II colon cancer were randomly assigned to 3- and 6-month treatment arms. The treatment consisted of either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine combined with oxaliplatin (CAPOX). The primary end point was disease-free survival (DFS). The secondary end points were treatment compliance and safety. RESULTS: Of the 525 randomized patients, 11 were not treated. Among the 514 participating patients (255 in the 3-month arm; 259 in the 6-month arm), 432 (84%) received CAPOX, and 184 (36%) presented with T4 as a high-risk factor for recurrence. The 3-year DFS rate was 88.2% in the 3-month arm and 87.9% in the 6-month arm [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.67-1.87]. With CAPOX, the 3-year DFS rate was 88.2% in the 3-month arm and 88.4% in the 6-month arm (HR, 1.13; 95% CI, 0.65-1.96). The discontinuation rate in the 3- and 6-month arms was 10% and 31% for mFOLFOX6 (P = 0.0193), and 15% and 35% for CAPOX (P < 0.0001), respectively. The incidence of grade ≥2 PSN was significantly lower in the 3-month arm than in the 6-month arm (16% and 43%, respectively, P < 0.0001). CONCLUSIONS: Three months of combination therapy presented significantly less grade ≥2 PSN than the respective 6-month regimen. The shortened therapy duration did not affect the 3-year DFS rate, suggesting that a 3-month course of CAPOX can be an effective treatment option. CLINICAL TRIAL INFORMATION: UMIN Clinical Trials Registry, UMIN000013036 and Japan Registry of Clinical Trials, jRCTs031180128.

Doctors' and nurses' attitudes towards and experiences of voluntary euthanasia: survey of members of the Japanese Association of Palliative Medicine.

OBJECTIVE: To demonstrate Japanese doctors' and nurses' attitudes towards and practices of voluntary euthanasia (VE) and to compare their attitudes and practices in this regard. DESIGN: Postal survey, conducted between October and December 1999, using a self-administered questionnaire. PARTCIPANTS: All doctor members and nurse members of the Japanese Association of Palliative Medicine. MAIN OUTCOME MEASURE: Doctors' and nurses' attitude towards and practices of VE. RESULTS: We received 366 completed questionnaires from 642 doctors surveyed (response rate, 58%) and 145 from 217 nurses surveyed (68%). A total of 54% (95% confidence interval (CI): 49-59) of the responding doctors and 53% (CI: 45-61) of the responding nurses had been asked by patients to hasten death, of whom 5% (CI: 2-8) of the former and none of the latter had taken active steps to bring about death. Although 88% (CI: 83-92) of the doctors and 85% (CI: 77-93) of the nurses answered that a patient's request to hasten death can sometimes be rational, only 33% (CI: 28-38) and 23% (CI: 16-30) respectively regarded VE as ethically right and 22% (CI: 18-36) and 15% (CI: 8-20) respectively would practise VE if it were legal. Logistic regression model analysis showed that the respondents' profession was not a statistically independent factor predicting his or her response to any question regarding attitudes towards VE. CONCLUSIONS: A minority of responding doctors and nurses thought VE was ethically or legally acceptable. There seems no significant difference in attitudes towards VE between the doctors and nurses. However, only doctors had practised VE.

Helicobacter pylori infection increases mucosal permeability of the stomach and intestine.

It is important to study the effect of Helicobacter pylori infection on the permeability of the intestine. Permeability was evaluated by oral sucrose tolerance test using sucrose 25 g in 200 ml of water. Existence of H. pylori itself was associated with increased permeability of sucrose. Also, the permeability of sucrose increased as polymorphonuclear and lymphocyte infiltration increased. The increase of mucosal permeability suggests that antigens like protein penetrate into the body and result in systemic reactions. Thus, it is important to study the implication of increased permeability in relation not only to gastric diseases but also certain systemic diseases.

Experimental gastric carcinogenesis related to Helicobacter pylori.

In this paper, we present our research on the lipid A of Helicobacter pylori, an experimental study using the Mongolian gerbil model and experimental carcinogenesis using the mouse model to evaluate roles of host factors and bacterial factors which are related to the pathogenicity of Helicobacter pylori including gastric carcinogenesis. Future study on bacterial factors and host factors may give more insight into the role of Helicobacter pylori in gastric carcinogenesis.

Influence of Helicobacter pylori infection on development of stress-induced gastric mucosal injury.

Immediately after the Great Hanshin Earthquake in Kobe in 1995, the recurrence rate of peptic ulcer in patients infected with Helicobacter pylori was higher than that in patients in whom H. pylori had been eradicated. We evaluated the influence of H. pylori infection on stress-induced gastric mucosal injury in Mongolian gerbils and C57BL/6 mice. These animals were immersed in water for 30, 120, and 720 min 12 weeks after inoculation with H. pylori, and then killed to assess gastric mucosal damage, and to measure cytokine production (interleukin [IL]-1beta, IL-4, IL-6, and IL-10; interferon [IFN]-gamma; and tumor necrosis factor [TNF]-alpha) in the gastric tissue of the mice. The stress treatment for 30 min resulted in a significantly higher bleeding rate and bleeding index among infected gerbils and mice compared with results in uninfected animals. Conversely, the bleeding and ulcer indexes were significantly higher in uninfected gerbils after 720 min of the stress treatment than in infected gerbils. Prior to the stress treatment, gastric IL-1beta and IFN-gamma production was significantly higher in the infected group than in the uninfected group. After 120 min of the stress treatment, TNF-alpha production was increased in the infected group, and IL-1beta and IL-10 production was increased in the uninfected group. However, the production of these cytokines showed no change at 30 min of the stress treatment. These results suggest that H. pylori infection influences the development of gastric mucosal injury in the early phase of stress exposure; cytokines do not play a major role in this process.

The view of religions toward euthanasia and extraordinary treatments in Japan.

388 Japanese religious groups--143 Shinto, 157 Buddhist, 58 Christian and 30 others--were asked to answer questions regarding several forms of euthanasia and extraordinary treatment during the dying process. Passive euthanasia and indirect euthanasia were accepted by around 70% of the respondents. Active euthanasia was favored by less than 20% of them. Christians were less supportive of euthanasia than practitioners of other religions. Shinto and Buddhist corporations advocated "being natural," when medical treatment became futile at the terminal stage. Religionists' views may deepen the discussion of end-of-life issues.

Effect of leukocytapheresis therapy using a leukocyte removal filter in Crohn's disease.

Eighteen patients with active Crohn's disease were treated with one leukocytapheresis session per week for a five-week intensive therapy, decreasing to one leukocytapheresis session per month for five sessions of initial maintenance therapy. Nutritional indices, inflammatory reactions, flow cytometry profiles, and cytokine production were also assessed before and after the intensive and initial maintenance therapy. Nine of the patients (50%) attained remission at the end of the intensive therapy. The nine non-remission patients had exhibited longer periods of suffering and more severely affected sites prior to the therapy. In 14 of 18 patients (77.8%), the nutritional indices, Internal Organization of Inflammatory Bowel Disease (IOIBD) score and Crohn's Disease Activity Index (CDAI) improved from the pretherapy levels, but only the remission group (50%) showed improvement in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The remission group showed significantly higher pretherapy CD4+ CD45+ cell ratios and interleukin-2 (IL-2) production than the non-remission group, and significantly lower activated cells.

Inhibitory effect of 1alpha-hydroxyvitamin D3 on N-methyl-N'-nitro-N-nitrosoguanidine-induced gastrointestinal carcinogenesis in Wistar rats.

The effect of 1alpha-hydroxyvitamin D3 (1alpha(OH)D3) on gastrointestinal carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in male Wistar rats. After oral treatment with 0.01% MNNG for 24 weeks, rats were given 0.04 microg of 1alpha(OH)D3 or its vehicle by gastric intubation three times a week for 24 weeks. The incidence of gastrointestinal tumors was 16/30 (53%) in rats treated with MNNG alone, 16/30 (53%) in those treated with MNNG plus vehicle and 8/30 (27%, P < 0.05) in those treated with MNNG plus 1alpha(OH)D3. The number of tumors per rat in the group treated with MNNG plus 1alpha(OH)D3 was half those in the control groups (P < 0.05). Results indicated that a non-hypercalcemic dose of 1alpha(OH)D3 had an inhibitory effect on MNNG-induced duodeno-intestinal carcinogenesis.

[Critical review on the WHO/IARC report regarding carcinogenicity of Helicobacter pylori].

Helicobacter pylori has been defined as a "definite carcinogen" at the WHO/IARC meeting in 1994. H. pylori causes histological gastritis. Long-lasting infection may induce atrophic gastritis, which is considered to be the first step in the gastritis-metaplasia-carcinoma sequence of the stomach. In a pooled analysis of the three prospective epidemiological studies, the relative risk for developing gastric cancer with H. pylori infection was 3.8, which was statistically significant. Thus, it was concluded that there was sufficient evidence in humans for the carcinogenicity of infection with H. pylori. However, there was no evidence experimentally for the carcinogenicity of infection with H. pylori. Further study is necessary to elucidate the role of H. pylori in gastric carcinogenesis.

What happened to elderly people in the great Hanshin earthquake.

The great Hanshin earthquake on 17 January 1995 hit the elderly population of an urban society particularly hard. More than half of the fatalities were among those over 60 years old, and in this age group female fatalities were almost double those of men. Surviving elderly people were largely left to their own devices and became relegated to the marginal space in shelters. Elderly people tended not to proclaim their problems, and so their suffering tended to be underestimated. Again, as survivors rebuilt their homes and moved back, elderly people and other vulnerable groups tended to be left behind in temporary accommodation. This tragedy has shown that special attention and continuous care is necessary for elderly and vulnerable people after such disasters.

Chemopreventive efficacy of low dose of pravastatin, an HMG-CoA reductase inhibitor, on 1,2-dimethylhydrazine-induced colon carcinogenesis in ICR mice.

Potential chemopreventive action of de-escalated doses of pravastatin (Pr), an HMG-CoA reductase inhibitor, on 1,2-dimethylhydrazine.2HCl (DMH)-induced colon tumorigenesis was evaluated in ICR mice. Thirty mice each in 4 groups received an intraperitoneal injection of 20 mg DMH/kg body weight once weekly for 10 weeks, and were given drinking water dissolved Pr at the concentration of 10 ppm, 5 ppm, or 0 ppm (control) throughout the experiment. The incidence of colon tumors examined at week 35 was significantly lower in the Pr-treated groups than the control group: 20%. 21% and 23% vs. 55%. However, the tumor multiplicity/tumor-bearing animal was increased in the Pr-treated groups compared to the control group. Of all the tumors, 66 were adenocarcinomas in the distal colon and 5 were squamous cell carcinomas at the anus. The Pr treatment showed no hypocholesterolemic effect but did significant decrease of colonic mucosal cholesterol. The results seems to suggest that a small dose of Pr may reduce the incidence of colon cancers, perhaps being related, at least in part, to modulation of cholesterol synthesis in situ at the colonic mucosa.

[Helicobacter pylori and gastric cancer].

H. pylori has been included as a definite biological carcinogen by WHO/ IARC. H. pylori is thought to play a role in the gastritis-metaplasia-carcinoma sequence by inducing atrophic gastritis. Clinical and epidemiological studies have shown a close association between H. pylori infection and gastric cancer. Yet, experimental evidence is equivocal. Epidemiological evidence also suggests that there are significant variable(s) other than H. pylori infection in gastric carcinogenesis. Clearly many questions regarding the role of H. pylori in gastric carcinogenesis have been left for further study. The authors have summarized these aspects together with their experimental results.

Difference in cytokine production in acute and chronic rejection of rat lung allografts.

In Brown Norway to Lewis rat lung transplantation, short-term administration of cyclosporine produces permanent adoption of allografts; however, the adopted grafts show symptoms of chronic rejection. To clarify the difference in cytokine production in acute an chronic rejection of the allografts, an immunohistochemical study was performed. In acute rejection, positive cells for respective cytokines were observed in infiltrating cells, increasing in number as the days after transplantation passed, and reaching a maximum on the fifth day. The strongest reactivity was observed perivenously. In chronic rejection, TNF-alpha positive cells were observed in the perivascular and peribronchial regions, especially around class II positive epithelia. The number of positive cells was, however, less than that in the vascular phase of acute rejection. Few cells were positive for IL-1 beta, IFN-gamma and, unexpectedly, for IL-4. These facts indicate the functional difference of infiltrating cells between acute and chronic rejection.

Leukocytapheresis therapy, performed with leukocyte removal filter, for inflammatory bowel disease.

Leukocytapheresis (LCAP), performed with a leukocyte removal filter, was administered five times, at 1-week intervals, for 5 weeks of intensive therapy and five times, at approximately 1-month intervals, for approximately 5 months of maintenance therapy, to 13 patients with inflammatory bowel disease (IBD) diagnosed as ulcerative colitis (UC) in 8 and Crohn's disease (CD) in 5. Clinical and blood examinations showed no side effects in any of the patients. During the intensive therapy, excellent or moderate clinical response was recognized in 11 of the 13 patients (84.6%), of whom 6 had a dramatic response; the excellent or moderate clinical response continued throughout the maintenance therapy in 8 of the patients (61.5%). Flow cytometry showed that the patients who had improved generally had high values for percentages of HLADR+, HLADR+CD3+, and HLADR+CD8+ cells before the first LCAP, and that these values and the C-reactive protein levels and erythrocyte sedimentation rates had decreased to the normal range by the end of both intensive and maintenance therapy. In the patients who showed poor response, in contrast, all the above values had been at or near normal before the initial LCAP administration. The clinical improvement in the absence of any additional medical treatment suggests that LCAP has the capacity to influence the causal mechanism(s) of IBD and that IBD is strongly associated with the cell-mediated immune response.