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Objectives: To determine whether the volume of paracentesis for malignant ascites in acute care hospital wards is associated with survival and symptom relief. Methods: Patients with malignant ascites caused by digestive system cancer who underwent paracentesis between January 2010 and April 2022 were retrospectively analyzed from medical records. Collected data included the drainage volume per paracentesis procedure, survival time from the first paracentesis procedure, symptoms, and adverse events. According to the volume per paracentesis procedure, we divided the patients into the “small-drainage” (≤1500 mL) and “standard-drainage” (>1500 mL) groups. Results: The median age of the 144 patients was 69 years, 33% were female, and 64% had gastrointestinal cancer. The median survival from the first paracentesis procedure was 36 days. Eighty-nine (61.8%) and 55 (38.2%) patients were allocated to the small-drainage and standard-drainage groups, respectively. The median number of paracentesis procedures in the small-drainage and standard-drainage groups was 12 and 7, respectively ( P=.001). The median survival in the small-drainage and standard-drainage groups was 50 and 44 days, respectively ( P=.76). The multivariate analysis showed that the amount of drainage per session was not significantly associated with survival. Symptoms improved similarly in the 2 groups. No serious adverse events were observed. Conclusions: Paracentesis was demonstrated to be effective and safe, irrespective of the amount of fluid drained, for patients with malignant ascites in an acute care hospital. Thus, a strategy of limiting the amount of drainage is not associated with longer survival.

Background Naldemedine, a novel peripherally-acting mu-opioid receptor antagonist, has improved opioid-induced constipation in randomized controlled trials. The most frequent adverse event of naldemedine is diarrhea, which can cause abdominal pain and often leads to treatment discontinuation. We aimed to identify risk factors and appropriate management strategies for key adverse events including diarrhea associated with naldemedine, since those have not been extensively studied. Methods We conducted a multi-center retrospective cohort study. Eligible patients had cancer, had undergone palliative care at participating centers, had been prescribed regular opioids, and had taken at least one dose of naldemedine between June 2017 and March 2018. The primary endpoint was the incidence of diarrhea according to baseline characteristics. Secondary endpoints included the duration of naldemedine administration, daily defecation counts before and after starting naldemedine, duration and severity of diarrhea as an adverse event of naldemedine, other adverse events, and the incidence of constipation within 7 days after recovery from diarrhea. We defined patients who started naldemedine within three days of starting a regularly prescribed opioid as the early group, and the remainder as the late group. Results Among 103 patients who received naldemedine, 98 fulfilled the eligibility criteria. The median age was 68 years and 48% of the patients were female. Median performance status was 3, and the median oral intake was 50%. The median duration of naldemedine administration and overall survival were 25 and 64 days, respectively. The incidence of diarrhea in the early group (n = 26) was significantly lower than in the late group (n = 72) (3.9% vs. 22.2%, p = 0.02). Daily defecation counts increased after late (median 0.43 to 0.88, p p = 0.34). Constipation after the diarrhea was resolved was common (53%), especially among patients who stopped naldemedine (78%). The diarrhea was improved within three days in 92% of patients who stopped other laxatives. Conclusions The early administration of naldemedine is beneficial because it reduces adverse events including diarrhea. Diarrhea caused by naldemedine can be effectively managed by stopping other laxatives while continuing naldemedine.

Opioids are effective in cancer pain management. However, adverse effects such as opioid-induced constipation(OIC) cause significant reductions in the quality-of-life of cancer patients. In addition, this treatment sometimes also results in inadequate pain relief. It is estimated that from 50-90% of cancer patients receiving opioids suffer from OIC. The mechanism of exogenous opioids on gastrointestinal opioid receptors is known to lead to bowel dysfunction: including motility, secretion and coordination of the sphincter function. The Rome Ⅳ criteria is widely used for the definition of OIC. Imaging, which is not routinely performed, is useful for diagnosing the severity and they also help in choosing the most appropriate laxatives. Additionally, the bowel function index (BFI)can help to distinguish between opioid-treated patients with or without constipation. Unfortunately, the effective Japanese scale for the BFI remains to be elucidated. Primary treatment with stimulants and osmotic laxatives often demonstrates limited effectiveness. New agents, such as peripherally acting mu-opioid receptor antagonists(PAMORA), which have a potent competitive antagonist action, are therefore needed to improve the treatment of such patients. PAMORA should be observed carefully for the diarrhea when the duration of opioid therapy is prolonged prior to PAMORA initiation. Pharmacologically, this diarrhea might be associated with the onset of peripheral withdrawal symptoms.

Parenteral morphine is widely used for dyspnea of imminently dying cancer patients, but the outcomes to expect over time remain largely unknown. We examined outcomes after the administration of parenteral morphine infusion over 48 h in cancer patients with a poor performance status. This was a multicenter prospective observational study. Inclusion criteria were metastatic/locally advanced cancer, ECOG performance status = 3–4, a dyspnea intensity ≥ 2 on a Support Team Assessment Schedule, Japanese version (STAS-J), and receiving specialized palliative care. After initiating parenteral morphine infusion, we measured dyspnea STAS-J as well as Memorial Delirium Assessment Scale (MDAS), item 9, and Communication Capacity Scale (CCS), item 4, every 6 h over 48 h. We enrolled 167 patients (median survival = 4 days). The mean age was 70 years, 80 patients (48%) had lung cancer, and 109 (65%) had lung metastases. The mean STAS-J scores decreased from 3.1 (95% confidence interval (CI) = 3.0–3.2) at the baseline to 2.1 (95%CI = 1.9–2.2) at 6 h, and remained 1.6–1.8 over 12–48 h. The proportion of patients with dyspnea relief (STAS-J ≤ 1) increased to 39% at 6 h, and ranged between 49 and 61% over 12–48 h. In contrast, up to 6.6 and 20% of patients showed hyperactive delirium (MDAS item 9 ≥ 2) and an inability to communicate (CCS item 4 = 3), respectively, over 48 h. Overall, terminal dyspnea was relatively well controlled with parenteral morphine, though a significant number of patients continued to suffer from dyspnea. Future efforts are needed to improve outcomes following standardized dyspnea treatment using patient-reported outcomes for imminently dying patients.

Although corticosteroids can relieve dyspnea in advanced cancer patients, factors predicting the response remain unknown. We aimed to explore potential factors predicting the response to corticosteroids for dyspnea in advanced cancer patients. In this preliminary multicenter prospective observational study, we included patients who had metastatic or locally advanced cancer, were receiving specialized palliative care services, and had a dyspnea intensity of ≥3 on a 0–10 Numerical Rating Scale (NRS) (worst during the last 24 h). The primary endpoint was NRS of dyspnea on day 3 after the administration of corticosteroids. Univariate/multivariate analyses were conducted to identify factors predicting ≥1-point reduction in NRS. Of 74 patients who received corticosteroids, 50 (68%) showed ≥1-point reduction in dyspnea NRS. Factors that significantly predicted the response were an age of 70 years or older (82 vs. 53%, p = 0.008), absence of liver metastases (77 vs. 46%, p = 0.001), Palliative Prognostic Index (PPI) ≤ 6 (90 vs. 61%, p = 0.041), presence of pleuritis carcinomatosa with a small collection of pleural effusions (84 vs. 55%, p = 0.011), presence of audible wheezes (94 vs. 60%, p = 0.014), and baseline dyspnea NRS ≥7 (76% vs. 52%, p = 0.041). In a multivariate analysis, factors predicting response included PPI

Context Although corticosteroids are widely used to relieve cancer-related fatigue (CRF), information regarding the factors predicting responses to corticosteroids remains limited. Objectives The aim of this study was to identify potential factors predicting responses to corticosteroids for CRF in advanced cancer patients. Methods Inclusion criteria for this multicenter, prospective, observational study were patients who had metastatic or locally advanced cancer and had a fatigue intensity score of 4 or more on a 0–10 Numerical Rating Scale (NRS). Univariate and multivariate analyses were conducted to identify the factors predicting two-point reduction or more in NRS on day 3. Results Among 179 patients who received corticosteroids, 86 (48%; 95% CI 41%–56%) had a response with two-point reduction or more. Factors that significantly predicted responses were performance status score of 3 or more, Palliative Performance Scale score more than 40, absence of ascites, absence of drowsiness, absence of depression, serum albumin level greater than 3 mg/dL, serum sodium level greater than 135 mEq/L, and baseline NRS score greater than 5. A multivariate analysis showed that the independent factors predicting responses were baseline NRS score greater than 5 (odds ratio [OR] 6.6, 95% CI 2.8–15.4), Palliative Performance Scale score more than 40 (OR 4.4, 95% CI 2.1–9.3), absence of drowsiness (OR 3.4, 95% CI 1.7–6.9), absence of ascites (OR 2.3, 95% CI 1.1–4.7), and absence of pleural effusion (OR 2.2, 95% CI 1.0–5.0). Conclusion Treatment responses to corticosteroids for CRF may be predicted by baseline symptom intensity, performance status, drowsiness, and severity of fluid retention symptoms. Larger prospective studies are needed to confirm these results.

It is important for cancer patients to receive end-of-life care at the desired place.To identify issues in selection of place for end-of-life care of cancer patients to realize their optimal survivorship.Between September 2015 and January 2016, a questionnaire consisting of 33 items, including end-of-life care place preferences, was administered to cancer patients who attended three university hospitals in Japan.A total of 971 questionnaires were collected (response rate, 88.4%). Fifty-eight percent of patients preferred to stay at home to receive end-of-life care. In contrast, more than 80% of patients did not know the details of healthcare services. The factors significantly associated with patients' choice for place of end-of-life care at home were "male gender" (odds ratio [OR] = 1.43, p = 0.030), "living in a one-person household" (OR = 0.21, p 0.001), "feeling close to friends" (OR = 0.94, p = 0.049), "thinking that the family is burdened" (OR = 0.55, p 0.001), "thinking that pain is controllable at home" (OR = 1.39, p 0.001), and "thinking that society should establish a system of home palliative care" (OR = 1.93, p 0.001).This study identified six factors influencing the selection of a place for end-of-life care. Most patients have a desire for a social system that allows end-of-life care at home where they can live with their family, but have anxiety about treatment to deal with symptom change, with concern about burden on their family. These issues should be addressed in the future.

In 2010s, several opioids became available in Japan, including methadone, tapentadol and hydromorphone. Methadone was approved in September 2012 by Japanese regulatory authority. Since methadone is positioned as so-calledstep 4 opioidin Japan, it must be prescribed as alternative opioid switched from another of 60mg/day or greater equivalent dose of oral morphine. Diversity of pharmacokinetics among individuals and various drug interactions require close monitoring of adverse events. In spite of these cautions, unique characteristics such as inhibiting N-methyl-D-aspartate(NMDA)and in- ducing internalization/degradation of mu-delta opioid receptor heterodimers underline the value of methadone in opioid switching. Tapentadol, a dual-acting opioid which inhibits noradrenaline(norepinephrine)reuptake, was approved in Japan in March 2014. In a double-blind randomized study comparing with oxycodone, tapentadol showed relatively better tolerability. Advantages such as having no active metabolites and minimal drug interactions also ease the administration of tapentadol to the patients with comorbidities. Hydromorphone, approved in March 2017, has a profile similar to morphine. Higher potency than morphine lead to less production of 3-glucronide metabolite(H3G)which accumulates in patients with renal failure and causes neurotoxicity. Because there is no concluding evidence about effect of hydromorphone on dyspnea or tolerability in patients with renal insufficiency, organized studies are still needed. We expect these "new in Japan" opioids contribute to long-term, stable pain control for patients with cancer.

Background: Hydromorphone is a standard opioid analgesic for cancer pain that, prior to this study, was not approved in Japan, where options for opioid switching are limited. We aimed to investigate the efficacy and safety of hydromorphone (DS-7113b) immediate-release tablets in opioid-naïve cancer patients with moderate to severe cancer pain., Methods: Multicenter, active-controlled, randomized, double-blind, parallel-group, non-inferiority study of 183 cancer patients over 20 years of age at 50 clinical sites in Japan. Hydromorphone tablets or oxycodone hydrochloride powder was orally administered four times daily for 5 days. The initial doses of hydromorphone and oxycodone hydrochloride were 4 mg/day and 10 mg/day, respectively, and adjusted as necessary. Efficacy was evaluated as the intergroup difference (95% confidence interval [CI]) of the least squares mean by analysis of covariance, using the baseline visual analog scale (VAS) as a covariate for change in VAS score at treatment completion/discontinuation in the full analysis set., Results: Non-inferiority of hydromorphone versus oxycodone was confirmed, with an intergroup difference (95% CI) in the least squares mean of −3.4 mm (−9.8 to 3.1 mm) for change in VAS scores, which was below the upper limit of the 95% CI at 10 mm, the non-inferiority limit determined during study planning. Adverse events occurred in 83.0% (73/88) of patients in the hydromorphone group and 77.4% (65/84) in the oxycodone group. The most frequently observed adverse events were somnolence, constipation, vomiting and nausea. Conclusions: The efficacy and safety of hydromorphone tablets are equivalent to those of oxycodone immediate-release powder.

Objective: To confirm the morphine to hydromorphone conversion ratio for hydromorphone (DS-7113b) immediate-release tablets in cancer patients who achieved pain control with oral morphine., Methods: This was a multicenter, active-controlled, randomized, double-blind, parallel-group, comparative study (July 2013 to December 2014) at 39 Japanese sites. Seventy-one patients (aged >20 years) who had achieved pain control with morphine 60 mg/day and 90 mg/day were randomly allocated 1:1 to hydromorphone immediate-release tablets at a dose converted at a hydromorphone:morphine ratio of 1:5 or 1:8, respectively, and treated for up to 5 days. The efficacy was evaluated as the pain control ratio., Results: The pain control ratio in the full analysis set was 83.3% (25/30) in the conversion ratio 1:5 group and 95.0% (38/40) in the conversion ratio 1:8 group, and both groups demonstrated highly successful pain control. The incidence of adverse events was 46.7% (14/30) in the conversion ratio 1:5 group and 58.5% (24/41) in the 1:8 group; the difference was not clinically relevant. Frequently observed adverse events (incidence ≥5%) were nausea, vomiting, diarrhea, somnolence and dyspnea., Conclusions: A high pain control ratio was maintained by a switch at either conversion ratio, and no notable difference was observed in the incidence of adverse events. A switch from morphine to hydromorphone is effective at a dose converted at ratios of 1:5 and 1:8.

Satoshi Inoue,1 Yoji Saito,2 Satoru Tsuneto,3 Etsuko Aruga,4 Azusa Ide,1 Yasuyuki Kakurai5 1Clinical Development Department, R&D Division, Daiichi Sankyo, Tokyo,2Department of Anesthesiology, Faculty of Medicine, Shimane University, Shimane, 3Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, 4Department of Palliative Medicine, School of Medicine, Teikyo University, Tokyo, 5Biostatistics and Data Management Department, R&D Division, Daiichi Sankyo, Tokyo, Japan Background: In Japan, there are limited options for switching opioid analgesics. Hydromorphone is an opioid analgesic that is routinely used instead of morphine for cancer pain; however, it is not yet available in Japan. The aim of this study was to assess the efficacy and safety of hydromorphone (DS-7113b) extended-release tablets in opioid-naïve patients with cancer pain not relieved by non-opioid analgesics.Subjects and methods: This was a multicenter, randomized, double-blind, parallel-group trial. A double-dummy method was used for blinding. Each randomized subject received either hydromorphone extended-release tablets plus placebo oxycodone hydrochloride extended-release tablets 4 mg/day (n=88) or placebo hydromorphone extended-release tablets plus oxycodone hydrochloride extended-release tablets 10 mg/day (n=93) orally for 7 days (once-daily dosing for hydromorphone and twice-daily dosing for oxycodone). The doses were adjusted as necessary. Efficacy was evaluated by change in visual analog scale (VAS) score from baseline to completion of treatment.Results: The between-group difference in least squares mean changes in VAS score from baseline to completion or discontinuation of treatment was −0.4 mm (95% CI −5.9 to 5 mm) by analysis of covariance where the baseline VAS score was used as a covariate. The upper limit of the 95% CI was below 10 mm, which was predefined as the noninferiority limit. This verified the noninferiority of hydromorphone tablets relative to oxycodone tablets. The incidence of adverse events was 80.7% (71 of 88) in the hydromorphone group and 83.7% (77 of 93) in the oxycodone group. The most common adverse events were nausea, vomiting, somnolence, diarrhea, and constipation, most of which are commonly observed with opioid analgesics.Conclusion: The efficacy and safety of hydromorphone extended-release tablets were equivalent to those of the oxycodone extended-release formulation. Keywords: hydromorphone, oxycodone, cancer pain, palliative medicine, double-blind study&nbsp

Pain is classified as either nociceptive pain, which results from a nociceptor stimulation, or neuropathic pain, which results from a lesion of the neural pathway. Clinically, in many cases, pain consists of a single origin but multiple origins are also possible. In this paper, we outline an assessment and strategy for nociceptive pain in cancer. The onset time, location, feature, strength, and etiology were included as categories for the assessment of pain. Furthermore, we added a psychosocial assessment to the physical assessment, which ensured comprehensive pain evaluation. We performed the investigation according to the WHO method for cancer pain relief. According to the effects and adverse effects, we chose a non-opioid analgesic and an opioid analgesic as medications. However, nonpharmacological therapy, such as radiotherapy and nerve block, is not a concern with the WHO analgesic ladder. It is important that a multi-disciplinary team, which includes physicians, nurses, physiotherapists, and pharmacists, support the patients to manage their pain by themselves through the knowledge of the factors affecting their pain and the medication methods for easing it when it gets worse. Although we cannot ease pain completely, it is important to define the goal of treatment with patients and to examine the strategy for maximum pain relief.

Corticosteroids are often used to treat fatigue and anorexia, but occasionally produce delirium. Information on the predictors of delirium in corticosteroid-treated cancer patients remains limited.To identify potential factors predicting the development of delirium in corticosteroid-treated cancer patients.An exploratory, multicenter, prospective, observational study.Inclusion criteria for this study were patients who had metastatic or locally advanced cancer and a fatigue or anorexia intensity score of 4 or more on a 0-10 Numerical Rating Scale.Univariate and multivariable analyses were performed to identify the predictors of delirium diagnosed by the Confusion Assessment Method (CAM) within three days of initiation of corticosteroids.Among 207 patients administered corticosteroids, 35 (17%; 95% confidence interval [CI] 12%-23%) developed at least one episode of delirium diagnosed by the CAM. Factors predictive of the development of delirium were as follows: Palliative Performance Scale ≤20, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 4, the Support Team Assessment Schedule (STAS) score of drowsiness1, concurrent opioid use, parenteral hydration volume ≤500 mL, and the absence of lung metastasis. A multivariable analysis identified the independent factors predicting responses as ECOG PS = 4 (odds ratio [OR] 4.0; 95% CI 1.7-9.3), STAS score of drowsiness1 (OR 3.4; 95% CI 1.4-8.2), and concurrent opioid use (OR 3.7; 95% CI 1.0-13).Delirium in corticosteroid-treated advanced cancer patients may be predicted by PS, drowsiness, and concurrent opioid use. Larger prospective studies are needed to confirm these results.

Although corticosteroids are widely used to relieve anorexia, information regarding the factors predicting responses to corticosteroids remains limited. The purpose of the study is to identify potential factors predicting responses to corticosteroids for anorexia in advanced cancer patients. Inclusion criteria for this multicenter prospective observational study were patients who had metastatic or locally advanced cancer and had an anorexia intensity score of 4 or more on a 0–10 Numerical Rating Scale (NRS). Univariate and multivariate analyses were conducted to identify the factors predicting ≥2-point reduction in NRS on day 3. Among 180 patients who received corticosteroids, 99 (55 %; 95 % confidence interval [CI], 47–62 %) had a response with ≥2-point reduction. Factors that significantly predicted responses were Palliative Performance Scale (PPS) > 40 and absence of drowsiness. In addition, factors that tended to be associated with ≥2-point reduction in NRS included PS 0–3, absence of diabetes mellitus, absence of peripheral edema, presence of lung metastasis, absence of peritoneal metastasis, baseline anorexia NRS of >6, presence of pain, and presence of constipation. A multivariate analysis showed that the independent factors predicting responses were PPS of >40 (odds ratio = 2.7 [95 % CI = 1.4–5.2]), absence of drowsiness (2.6 [1.3–5.0]), and baseline NRS of >6 (2.4 [1.1–4.8]). Treatment responses to corticosteroids for anorexia may be predicted by PPS, drowsiness, and baseline symptom intensity. Larger prospective studies are needed to confirm these results.

Context Although an evidence-based clinical guideline for parenteral hydration therapy was established in Japan, the efficacy of the guideline has not been assessed. Objectives Our purpose was to explore the effect of parenteral hydration therapy based on this clinical guideline on quality of life (QoL), discomfort, symptoms, and fluid retention signs in patients with advanced cancer. Methods This multicenter, prospective, observational study included 161 patients with advanced abdominal cancer who received guideline-based hydration therapy. We evaluated the longitudinal changes of the global QoL (Item 30 of European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-C30); the Discomfort Scale; the intensity of seven physical symptoms; and the severity of fluid retention signs. We also evaluated patient satisfaction and the feeling of benefit from hydration one week after the study commenced, and bronchial secretions, hyperactive delirium, communication capacity, and agitation 48 hours before a patient's death. Results The global QoL, the Discomfort Scale, and the intensities of all physical symptoms, except for vomiting and drowsiness, were stable throughout the study period. More than 80% of patients maintained all fluid retention signs. Patient global satisfaction was 76.4 (0–100) and feeling of benefit was 5.43 (range 0–7). Conclusion Guideline-based parenteral hydration therapy contributed to maintaining global QoL and provided satisfaction and a feeling of benefit without increasing discomfort and worsening symptoms and fluid retention signs in patients with advanced cancer.

【目的】今回, 門脈高度狭窄症例において経口投与されたオピオイドにより予測を超えた傾眠を呈し, 投与経路変更にて改善した1例を経験したので報告する. 【症例】下部胆管がんの術後局所再発およびリンパ節転移により門脈高度狭窄をきたした60歳代女性に, 外科で経口オキシコドン徐放錠剤10mg/日が投与され, 傾眠が出現したため当科に診察依頼があった. 生体利用率は低いが分割投与が可能な散剤を用いて, 経口モルヒネ徐放剤10mg/日に切り替え, さらに投与量を5mg/日に減量したが, 傾眠は持続した. これをフェンタニル貼付剤2.5mg半面貼付に変更したところ, 症状が改善した. 【結論】門脈血流低下症例では, 初回通過効果を受けないために経口オピオイド製剤の血中濃度が上昇する可能性があり, 投与時に十分な観察が必要である. また, 経口から経皮へのオピオイド投与経路変更が血中濃度上昇に伴う副作用の改善に有用である可能性が示唆された. Palliat Care Res 2008; 3(2): 331-334

The antitumor effect and mechanisms activated by murine IL-12 and IL-18, cytokines that induce IFN-gamma production, were studied using engineered SCK murine mammary carcinoma cells. In syngeneic A/J mice, SCK cells expressing mIL-12 or mIL-18 were less tumorigenic and formed tumors more slowly than control cells. Neither SCK.12 nor SCK.18 cells protected significantly against tumorigenesis by distant SCK cells. However, inoculation of the two cell types together synergistically protected 70% of mice from concurrently injected distant SCK cells and 30% of mice from SCK cells established 3 d earlier. Antibody neutralization studies revealed that the antitumor effects of secreted mIL-12 and mIL-18 required IFN-gamma. Interestingly, half the survivors of SCK.12 and/or SCK.18 cells developed protective immunity suggesting that anti-SCK immunity is unlikely to be responsible for protection. Instead, angiogenesis inhibition, assayed by Matrigel implants, appeared to be a property of both SCK.12 and SCK.18 cells and the two cell types together produced significantly greater systemic inhibition of angiogenesis. This suggests that inhibition of tumor angiogenesis is an important part of the systemic antitumor effect produced by mIL-12 and mIL-18.

Interferon-gamma-inducing factor (IGIF) is a novel cytokine that stimulates T-cell proliferation, augments natural killer (NK) cell lytic activity, and induces interferon-gamma (IFN-gamma) production in established type 1 T-helper (Th1) cells in the presence of anti-CD3 antibody. The in vitro induction of IFN-gamma by recombinant murine IGIF in these cells was more potent than that induced by murine interleukin-12 (IL-12) and occurred apparently independent of murine IL-12. Here we report that subcutaneous injection into mice of tumor cells transfected with murine IGIF complementary DNA (cDNA) resulted in > or = 10-fold increase of mitogen-stimulated IFN-gamma production in cultured splenocytes. In addition, IGIF-transfected Renca and K1735 tumor cells can be rejected in vivo. The IGIF antitumor effect was abrogated in mice that were sublethally irradiated or depleted of both CD4+ and CD8+ T cells but not in mice depleted of either subpopulation alone. The antitumor effect mediated by IGIF appears to be dependent on IFN-gamma production, because in vivo neutralization of IFN-gamma was accompanied by growth of IGIF-transfected tumors in 100% of the animals. Taken together, our results show that murine IGIF can elicit T-cell-dependent antitumor immunity associated with IFN-gamma induction.

We have previously demonstrated that the growth of weakly immunogenic murine sarcomas leads to the induction of immunologically specific preeffector cells in tumor-draining lymph nodes (TDLN). The in vitro activation of TDLN cells with anti-CD3 monoclonal antibodies (mAbs) and interleukin-2 (IL-2) resulted in the acquisition of effector function as measured by tumor regression in the adoptive immunotherapy of pulmonary metastases. Further studies were performed to characterize the mechanisms associated with in vivo tumor reactivity mediated by activated TDLN cells. By positive selection, CD4+ and CD8+ T cells were purified and activated by the anti-CD3/IL-2 method. CD8+, but not CD4+, cells manifested tumor-specific granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ (IFN-γ) release in vitro, and elicited tumor regression in vivo. By contrast, only activated CD4+ were found to release significant amounts of IL-2 in response to tumor antigen but did not mediate tumor regression in vivo. Mixing the two purified populations enhanced the antitumor activity of the CD8+ T cells. In culture, IL-2 was found to augment the relative amount of tumor-specific release of GM-CSF and IFN-γ by activated TDLN cells. We found that the tumor-specific release of GM-CSF and IFN-γ by activated lymphocytes was strongly associated with the in vivo therapeutic efficacy of these cells. Evidence in support of this included the following: (1) cytokine release of TDLN derived after different durations of tumor growth correlated with tumor reactivity in adoptive transfer studies, (2) cytokine release of T cells derived from different lymphoid organs corresponded with tumor reactivity in adoptive transfer, and (3) in vivo administration of neutralizing mAb to IFN-γ and GM-CSF significantly inhibited the antitumor reactivity of TDLN cells. These studies document the contributory roles of IFN-γ, GM-CSF, and IL-2 released by activated CD4+ and CD8+ T cells involved in tumor regression.

Background Under-diagnosis of pain is a serious problem in cancer care. Accurate pain assessment by physicians may form the basis of effective care. The aim of this study is to examine the association between late referral to a Palliative Care Team (PCT) after admission and the under-diagnosis of pain by primary physicians. Methods This retrospective study was performed in the Teikyo University teaching-hospital for a period of 20 months. We investigated triads composed of 213 adult cancer inpatients who had coexisting moderate or severe pain at the initial PCT consultation, 77 primary physicians, and 4 palliative care physicians. The outcome of the present study was the under-diagnosis of pain by primary physicians with routinely self-completed standard format checklists. The checklists included coexisting pain documented independently by primary and palliative care physicians at the time of the initial PCT consultation. Under-diagnosis of pain was defined as existing pain diagnosed by the palliative care physicians only. Late referral to PCTs after admission was defined as a referral to the PCT at ≥20 days after admission. Because the two groups displayed significantly different regarding the distributions of the duration from admission to referral to PCTs, we used 20 days as the cut-off point for “late referral.” Results Accurate pain assessment was observed in 192 triads, whereas 21 triads displayed under-diagnosis of pain by primary physicians. Under-diagnosis of pain by primary physicians was associated with a longer duration between admission and initial PCT consultation, compared with accurate pain assessment (25 days versus 4 days, p Conclusions Under-diagnosis of pain by primary physicians was associated with late referral to PCTs. Shortening the duration from admission to referral to PCTs, and increasing physicians’ awareness of palliative care may improve pain management for cancer patients.

Cancer-related pain affects approximately 90% of those in all stages of the disease. Pain is both a sensation and an emotional experience, and thus it has been defined as total pain. The type of cancer pain management decided upon depends on the underlying pathophysiological mechanisms, which are classified as nociceptive(somatic and visceral), neuropathic, and idiopathic. Pain management as part of routine cancer care has been forcefully advanced by the World Health Organization( WHO)-analgesic ladder. The clinical application of pain management should be employed only after a complete and comprehensive assessment and evaluation. The present overview article focuses on nonsteroidal anti-inflammatory drugs (NSAIDs), opioids and adjuvant analgesia.

Background Continual collaboration between physicians and hospital-based palliative care teams represents a very important contributor to focusing on patients' symptoms and maintaining their quality of life during all stages of their illness. However, the traditionally late introduction of palliative care has caused misconceptions about hospital-based palliative care teams (PCTs) among patients and general physicians in Japan. The objective of this study is to identify the factors related to physicians' attitudes toward continual collaboration with hospital-based PCTs. Methods This cross-sectional anonymous questionnaire-based survey was conducted to clarify physicians' attitudes toward continual collaboration with PCTs and to describe the factors that contribute to such attitudes. We surveyed 339 full-time physicians, including interns, employed in a general acute-care hospital in an urban area in Japan; the response rate was 53% (N = 155). We assessed the basic characteristics, experience, knowledge, and education of respondents. Multiple logistic regression analysis was used to determine the main factors affecting the physicians' attitudes toward PCTs. Results We found that the physicians who were aware of the World Health Organization (WHO) analgesic ladder were 6.7 times (OR = 6.7, 95% CI = 1.98-25.79) more likely to want to treat and care for their patients in collaboration with the hospital-based PCTs than were those physicians without such awareness. Conclusion Basic knowledge of palliative care is important in promoting physicians' positive attitudes toward collaboration with hospital-based PCTs.

This paper reviews current cancer pain management guidelines, the challenge of managing pain across the care settings hospital to home. This also presents up-to-date information on the medications and strategies and the expansion of the World Health Organization's (WHO) analgesic ladder with several classes of drugs that are currently used to treat cancer pain: (1) non-steroidal anti-inflammatory drugs (NSAIDs), (2) opioid analgesics with opioid rotation and the control for side effect of opioid, (3) adjuvant analgesics including ketamine.

Diseases, details of interventions, medical cares provided and the condition of use and services of local medical institutions were investigated in the home care support activities during the period from November 1997 to March 2003. We intervened in 1,309 patients. 70% of them were terminal patients with malignant tumor. Interventions were mostly consultations about the life under medical care, guidance about HPN/tube feeding, consultations about nursing and coordination with local medical institutions. 422 of them were under care of family doctors. 502 of them used visiting nursing. 70% of the patients under care of the hospital required high-tech home care and home hospice care. The 5-year activities indicate that nurses who support home care at the hospitals providing acute medical care are expected to (1) serve as the consultation contact for patients and families, (2) support the life under medical care in consultation with internal and external related professionals, (3) use social resources, (4) serve as the contact for providing the logistic support under an emergent situation or under the lack of care-giving capabilities, (5) provide guidance for the safe use of high-tech home medical care by patients/families at the discharge, (6) communicate or coordinate with local medical institutions for continued care/nursing and (7) develop/support the flexible and convenient distribution system of medical equipment and medical materials/drugs or the 24 hour healthcare support system jointly with private enterprises.

As a medical advisor specialized in palliative care, I think the following points should be considered regarding management of patients after discharge from a tertiary hospital: (1) Information that we should get before the interview and examination, (2) Assessment of symptoms, (3) Medications for the management of pain, (4) Supportive care to cope with psychosocial problems derived from the management of physical symptoms, (5) Help to continue with activities of daily life and to cope with the cancer at home, and (6) Characterize of the medical advisor as a member of an interdisciplinary team.

Seventy-nine terminal patients with gynecological cancer treated in the past 5 years in our hospital or their families were interviewed on where those patients died and the reason why they chose to die in the place. Fifty-two patients (65.8%) were died at our hospital, 18 patients (22.8%) at other hospitals, 5 (6.3%) at other hospice and 4 (5.1%) at home. The 52 patients who died at our hospital were asked why they chose to die there. 42 of them (80.8%) wanted care at our hospital to the death. 10 (20.2%) had no time to think of home care or other institutions because of the sudden change of the condition. The 18 patients who died at other institutions were also asked about the reason. 9 of them (50%) wanted to die in their hometown or close to their home. 5 of them (27.8%) were referred to other hospitals due to brain metastasis or the necessity of undergoing dialysis. 2 of them (11.1%) were referred to the institutions which provide long-term care. 2 of them (11.1%) were brought into a nearby emergent care hospital and died after the sudden change of the condition. The palliative care ward in our university hospital can provide continued relationship with cancer patients. We had time to talk enough with carcinoma patients and their family in the ward, which widened choices of their death place, including home death.

We report a case of recurrent breast cancer with chronic renal failure in a 58-year-old female. She could be treated on an outpatient basis under good general condition for most of her remaining life by chemoradiotherapy in combination with hemodialysis. Modification of the chemoradiotherapy procedures and collaboration of medical staff including the doctor in charge of home medical care and her family was indispensable in keeping her hospital stay as short as possible.

Context The many benefits of hospital palliative care teams (PCTs) are well known. However, their specific activities have not been fully clarified, and no standardized methods for reporting PCT activities are available. Objectives The aim of this study was to investigate, through the use of a standard format, the activities performed by hospital PCTs in Japan. Methods This was a prospective observational study. A total of 21 hospital PCTs were included in this study, and each recruited approximately 50 consecutively referred patients. Participating PCTs filled in a standard form for reporting activities. Results We obtained data from 1055 patients who were referred to PCTs. Of the 1055 patients, 1005 patients (95%) had cancer. The median number of reasons for referral and problems identified by PCTs was two (0–22) and four (0–18), respectively. The two major reasons for referral were pain (63%) and anxiety/depression/grief/emotional burden (22%). The major recommendations were pharmacological treatment (74%), care for the patient's physical symptoms (49%), and support for patient's decision making (38%). The major activities performed by the PCTs were comprehensive assessment (90%), care for the patient's physical symptoms (77%), and pharmacological treatment (74%). Conclusion The components of hospital PCT activities were successfully measured using the Standard Format for Reporting Hospital PCT Activity. The results of this study and the format for reporting hospital PCT activity could be effective in improving hospital PCT practice and for the education of new hospital PCT members.

The authors examined cellular mechanisms involved in anti-tumor reactivity induced by the murine MT-9G1 mammary tumor line, which was transduced to secrete granulocyte macrophage-colony-stimulating factor (GM-CSF). Compared with the parental MT-901 tumor, MT-9G 1 subcutaneous tumors elicited an influx of CD4 + cells and dendritic cells. Secondary in vitro activation of tumor-draining lymph node cells with anti-CD3 and interleukin-2 resulted in effector cells that can mediate regression of established pulmonary metastases after adoptive transfer. In vivo depletion of T-cell subsets showed that tumor regression required CD4 + tumor-draining lymph node cells rather than CD8 + cells. The activated CD4 + cells expressed CD95L and mediated lysis of CD95 + MT-901 tumor cells, which were major histocompatibility complex class II negative. The CD4 + cells also released GM-CSF in response to tumor stimulation. A Fas fusion protein inhibited tumor lysis and GM-CSF release by the CD4 + cells. These studies document an alternate pathway by which CD4 + immune cells may recognize major histocompatibility complex class II-deficient tumors in which CD95L-bearing T cells induced an anti-tumor response mediated via CD95L:CD95.

Using the poorly immunogenic D5 murine melanoma, we examined the adjuvant effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-12 (IL-12) secretion by gene-modified tumor cells inoculated as a vaccine to prime tumor-draining lymph nodes (TDLNs). D5 transfectants that secreted IL-12 or GM-CSF alone were compared with a double transfectant that secreted equivalent amounts of both cytokines. TDLN cells harvested 9 ‐10 days after subcutaneous tumor inoculation were cultured sequentially in anti-CD3 and IL-2 and assessed for antitumor reactivity against wild-type D5 tumor. The double transfectant-induced TDLN effector cells had greater cytotoxicity in a long-term assay than TDLN cells primed by single transfectants. In adoptive immunotherapy, the TDLN cells primed by the double transfectant were significantly better at mediating the regression of established tumors compared with the TDLN cells elicited by the single transfectants. Both IL-12 and GM-CSF had adjuvant effects in promoting tumor-reactive TDLN cells, but the combination was better than either alone. These observations suggest that the immunomodulation roles of IL-12 and GM-CSF are different and complementary.