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Background: The risk of Parkinson's disease (PD)-related death in patients with cancer largely unexplored., Methods: We analyzed data from the Neoplasms ANd other causes of DEath (NANDE) study, which investigates the causes of death in patients with cancer in Japan. Standardized mortality ratios (SMRs) were calculated to compare the risk of PD-related deaths in patients with cancer to that of the general population. Poisson regression models were employed to estimate the relative risk of PD-related death in the subgroups., Results: The cohort included 548,485 patients with cancer, yielding 2,047,398 person-years at risk from 1995 to 2013. During the study period, 242,250 patients died and 145 deaths were attributable to PD. The SMR for PD-related death was 2.34 (95% confidence interval [CI]: 1.99-2.75). Patients who were diagnosed with cancer before 70 years of age had a high SMR (>5) for PD-related deaths. The SMR of patients with mouth-to-stomach cancers (lip, oral cavity, pharynx, esophagus, and stomach cancers) was 3.72 (95% CI: 2.84-4.86), while that of those with other cancers was 1.93 (95% CI: 1.57-2.37). The multivariate Poisson regression model revealed that patients with mouth-to-stomach cancers were more likely to die of PD than those without (relative risk 2.07, 95 % CI; 1.46-2.93)., Conclusions: Patients with cancer are at a high risk of PD-related death; particularly, mouth-to-stomach cancers and potentially obstructing medication for PD are attributable to a high mortality risk. Careful management, including adequate PD treatment, would benefit cancer survivors with PD and reduce the risk of PD-related death., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Data on the risk of cardiovascular-related mortality in patients with cancer are limited., Methods and Results: This retrospective cohort study used data from the Osaka Cancer Registry and vital statistics in Japan between 1985 and 2013. The causes of death were investigated, and the risk of fatal heart disease was analyzed. Standardized mortality ratios were calculated to compare the risk of fatal heart disease between patients with cancer and the general population. Fine and Gray competing risk regression models were used to assess the risk of fatal heart disease among patients with cancer. In total, 682 886 patients with cancer were included in the analysis, and 335 635 patients died during the study period. Heart disease was the leading cause of noncancer deaths, with 10 686 deaths. Among the patients who died of heart disease, 5017 had ischemic heart disease, 3598 had heart failure, 356 had hypertensive disease, and 1715 had other heart diseases. The standardized mortality ratio for heart disease was 2.80 (95% CI, 2.74-2.85). The standardized mortality ratio for ischemic heart disease, heart failure, and hypertensive disease were 3.26 (95% CI, 3.17-3.35), 2.69 (95% CI, 2.60-2.78), and 5.97 (95% CI, 5.38-6.63), respectively. The risk of fatal heart disease increased over time after cancer diagnosis. Men were more likely to die of heart disease than women (subdistribution hazard ratio, 1.08 [95% CI, 1.02-1.16]). The risk of fatal heart disease among cancer survivors has decreased in recent years., Conclusions: Cancer survivors have a higher risk of fatal heart disease than the general population.

Centralization of childhood cancer treatment in specialized hospitals is necessary for quality treatment and care, but imposes a time and cost burden for patients and their families. We investigated the 20-year trend in the patients' car travel burden to reach cancer-care hospitals in Aichi Prefecture, Japan. From the Aichi population-based cancer registry data, 1,741 cases diagnosed in 1998-2017 under 15 years of age were extracted and assigned to three treatment groups: invasive treatment (n = 697), radiotherapy (n = 371), or chemotherapy groups (n = 1,462), allowing for duplicate assignment. Their travels to access each treatment hospital were estimated and summarized as the estimated travel times (ETT), estimated travel distances (ETD), and direct distances (DD). The ETTs were compared using the Brunner-Munzel test. The average cases per year for each hospital were plotted. The annual trends during 1998-2017 on ETT, ETD, and DD were investigated using Joinpoint regression models. The ETTs were 0.38-0.45 hours on median for three periods (1998-2005, 2006-2012, and 2013-2017) in three treatment groups and increased by 0.02-0.07 hours from 2006-2012 to 2013-2017, with a statistically significant difference in the radiotherapy group (0.07 hours, P = 0.037). The average cases per year increased for the top hospital in each group, and regression model analyses showed no joinpoint on the annual median trend. In conclusion, the increases in travel times were small and not considered clinically significant, and treatment centralization was observed from 2006-2012 to 2013-2017., Competing Interests: The authors have no conflicts of interest to declare for this study.

Immune checkpoint inhibitors highlight the importance of anticancer immunity. However, their clinical utility and safety are limited by the low response rates and adverse effects. We focused on progesterone (P4), a hormone produced by the placenta during pregnancy, because it has multiple biological activities related to anticancer and immune regulation effects. P4 has a reversible immune regulatory function distinct from that of the stress hormone cortisol, which may drive irreversible immune suppression that promotes T cell exhaustion and apoptosis in patients with cancer. Because the anticancer effect of P4 is induced at higher than physiological concentrations, we aimed to develop a new anticancer drug by encapsulating P4 in liposomes. In this study, we prepared liposome-encapsulated anti-programmed death ligand 1 (PD-L1) antibody-conjugated P4 (Lipo-anti-PD-L1-P4) and evaluated the effects on the growth of MDA-MB-231 cells, a PD-L1-expressing triple-negative breast cancer cell line, in vitro and in NOG-hIL-4-Tg mice transplanted with human peripheral blood mononuclear cells (humanized mice). Lipo-anti-PD-L1-P4 at physiological concentrations reduced T cell exhaustion and proliferation of MDA-MB-231 in vitro . Humanized mice bearing MDA-MB-231 cells expressing PD-L1 showed suppressed tumor growth and peripheral tissue inflammation. The proportion of B cells and CD4+ T cells decreased, whereas the proportion of CD8+ T cells increased in Lipo-anti-PD-L1-P4-administrated mice spleens and tumor-infiltrated lymphocytes. Our results suggested that Lipo-anti-PD-L1-P4 establishes a systemic anticancer immune environment with minimal toxicity. Thus, the use of P4 as an anticancer drug may represent a new strategy for cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kametani, Ito, Ohshima, Manabe, Ohno, Shimizu, Yamada, Katano, Kirigaya, Ito, Matsumoto, Tsuda, Kashiwagi, Goto, Yasuda, Maeki, Tokeshi, Seki, Fukase, Mikami, Ando, Ishimoto and Shiina.)

Background: The incidence of de novo malignancy (DNM) after liver transplantation (LT) is reported to be 3.1% to 14.4%. It is a known cause of death in long-term recipients. This study aimed to clarify the clinical features and risk factors of DNM., Methods: Recipients who underwent adult-to-adult living-donor LT (LDLT) and survived for >6 months were investigated. The medical records were retrospectively reviewed. This study was approved by the institutional review board., Results: In total, 180 patients were included. The indications for LDLT were hepatocellular disease (n = 62), metabolic liver disease (n = 50), cholestatic disease (n = 46), acute liver failure (n = 12), and others (n = 10). The median age at LDLT was 48 (18-71) years, and the follow-up period was 15 (0-29) years. De novo malignancy was diagnosed in 24 recipients (28 sites), including the digestive tract (n = 9), genitourinary (n = 5), gynecologic (n = 5), lung (n = 4), hematological (n = 3), and others (n = 2). The median duration from LDLT to DNM was 7 (0-19) years. Four patients were lost to follow-up due to advanced-stage cancer. R0 (curative treatment) for non-hematological DNM was achieved in 19 lesions (95%). The 10- and 20-year DNM incidence rates were 11% and 20%, respectively. The 20-year survival rates of DNM (59.6%) and non-DNM (59.9%) patients were not significantly different. De novo malignancy was significantly higher in patients with primary sclerosing cholangitis than in others (P < .05)., Conclusions: Even in DNM recipients, early detection of malignancy and R0 treatment promises long-term outcomes comparable to those of non-DNM recipients., Competing Interests: DISCLOSURES All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Worldwide, research based on geographic information of official statistical data, including cancer registries, is utilized for cancer control and public health policies. The National Cancer Registry of Japan was launched in 2016, making it possible to use data on cancer incidence systematically. Given the nature of this comprehensive survey, the usefulness of the National Cancer Registry would be further enhanced when it is utilized at small-regional levels, such as in municipalities or even smaller geographical units. It is essential to maintain a balance between privacy protection and data usability. Currently, the national and prefectural councils determine the availability of the data from the National Cancer Registry at the small-regional level on an individual application basis. Under this framework, use of the data is often restricted or declined. This paper showcases three model countries where geographic information obtained from cancer registry data are widely utilized: the United States, Canada, and the United Kingdom. It further discusses measures to ensure that data are effectively used, without compromising data privacy. In the three countries, data-providing systems have been established to compile the necessary data from the cancer registry and other linked databases, in accordance with the purpose of use. The relationships between healthcare access and various outcomes are elaborately examined at the small-regional level. In Japan, similar utilization of data has not been fully implemented, and there remain many hurdles to the application of the data use. For the National Cancer Registry to promote research and further enhance cancer control, it is necessary to establish a system that enables effective and safe utilization of the data from the National Cancer Registry, including linkage with other data and on-site use.

Introduction: The association between cancer survivors and stroke deaths remains unclear. We aimed to evaluate the risk of fatal stroke in patients with cancer., Materials and Methods: This study was conducted using data from the Osaka Cancer Registry and vital statistics in Japan, collected from 1985 to 2013. We extracted patient data and investigated the causes of death. Standardized mortality ratios were calculated to compare the risk of stroke in patients with cancer to that in the general population. Poisson regression models were used to estimate the risk of stroke in patients with cancer and other cancer subgroups. Stroke types were used for risk stratification., Results: We identified 688,473 eligible patients with cancer. The cohort contributed 2,668,126 person-years at risk. During the study period, 337,117 patients died; stroke was the cause of death in 5496 patients. Stroke types included cerebral infarction (3259), intracerebral hemorrhage (1539), subarachnoid hemorrhage (364), and other cerebrovascular diseases (334). The crude mortality rate from fatal stroke was 205.99 per 100,000 person-years. The standardized mortality ratio (95 % confidence interval) for fatal stroke was 1.75 (1.71-1.80). When stratified by stroke types, the ratios for cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage were 1.83 (1.76-1.89), 2.38 (2.26-2.50), and 2.28 (2.03-2.56), respectively. The risk of fatal stroke increased with time after cancer diagnosis. The multivariate Poisson regression model indicated that men were more likely to die of stroke than women., Conclusions: Cancer survivors have a higher risk of fatal stroke than the general population across all stroke types., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/aim: Benzimidazoles are considered potential anticancer candidates. We herein studied the anticancer activity of CCL299, 4-(1H-1,3-benzodiazol-1-yl) benzonitrile., Materials and Methods: In this in vitro study, we used ATP assays, flow cytometry, western blotting, and caspase-3/7 assays to evaluate the effects of CCL299 on cell proliferation, cell-cycle progression and apoptosis., Results: ATP assays showed that CCL299 inhibited cell growth in the hepatoblastoma cell line HepG2 and the cervical cancer cell line HEp-2, without exhibiting cytotoxic effects on non-cancer cells and TIG-1-20 fibroblasts. Flow cytometry, western blotting, and caspase-3/7 assays revealed that CCL299 induced G 1 -phase cell-cycle arrest followed by apoptosis that was associated with up-regulation of p-p53 (Ser15) and p21 expression and the down-regulation of p-CDK2 (Thr160) expression., Conclusion: CCL299 exhibits cytotoxic activity via apoptosis in a subset of cancer cells, and should be considered as a promising anticancer candidate agent., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Targeting cell‑cycle regulation to hinder cancer cell proliferation is a promising anticancer strategy. The present study investigated the effects of a novel sulfonamide, CCL113, on cell cycle progression in cancer cell lines (HeLa and HepG2), a noncancerous cell line (Vero) and a normal human fibroblast cell line (TIG‑1‑20). The present results showed that treatment with CCL113 significantly decreased the viability of the cancer cells. FACS analyses showed that CCL113 treatment increased the proportion of cancerous and noncancerous cells in the G2/M phase. Analyses of cell cycle regulatory proteins showed that CCL113 treatment inhibited the activity of CDK1 in HeLa cells, possibly due to the decrease in the level of Cdc25B/C proteins and arrest in the M phase. Using time‑lapse imaging‑assisted analyses of HeLa and Vero cells expressing fluorescent ubiquitination‑based cell cycle indicator (FUCCI), it was observed that CCL113 treatment led to a prolonged G2 phase at the G2/M checkpoint and arrest in the M phase in both cell lines. This possibly activated the DNA damage response in noncancerous cells, while inducing mitotic arrest leading to apoptosis in the cancer cells. The results of molecular docking studies suggested that CCL113 might have the potential to bind to the taxol‑binding site on β‑tubulin. In conclusion, CCL113 holds potential as a reliable anticancer drug due to its ability to induce mitotic arrest followed by apoptosis of cancer cells and to activate the DNA damage response in noncancerous cells, thereby facilitating exit from the cell cycle.

Cell senescence is caused by the activation of cell cycle inhibition pathways induced by an accumulation of cellular damage, where cells permanently leave the cell cycle. Senescent cells undergo changes in cell morphology, transcription, protein homeostasis, metabolism and other characteristic alterations. At the same time, senescent cells are able to resist apoptosis and accumulate in multiple organs and tissues in vivo. Senescent cells are capable of activating inflammatory factor secretion pathways, generating local, non‑infectious inflammatory microenvironments within tissues, leading to organ degeneration and the development of aging‑associated diseases. A large number of recently published studies have demonstrated that removing senescent cells from the body delays the occurrence of various aging‑associated diseases. Therefore, the targeted killing of senescent cells potentially has important clinical applications in the treatment of various aging‑associated diseases, aiming to improve the life span of patients. The present review summarizes recent progress that has been made in the field of senescent cell clearance and various anti‑aging strategies. The history of cell senescence research is briefly reviewed, along with the association between cell senescence and tumor therapy. Furthermore, the potential of senescent cells to be used as therapeutic targets in various senescence‑associated diseases is primarily discussed, and the limitations, as well as the future prospects of this line of research, are reviewed.

Objective: In 2013, 15 childhood cancer hub hospitals in Japan were designated to provide quality medical treatment and care. The present study assessed hospital accessibility by investigating travel times and distances from patient residences., Methods: A total of 37,309 residence/hospital pairs were generated using the addresses of 15 hub hospitals that were designated in 2019 and local government offices in 2014. Using the Google Directions Application Programming Interface (API), travel times and distances were calculated on the assumption that each patient would arrive by driving to the hospitals by 10 am on Wednesday, November 6, 2019. Thus, after identifying the nearest hospital for each residence and deriving adjusted estimated travel times (AETT), the data were summarized according to the regional block using weighted population descriptive statistics for children under 15 years of age in 2015. The cumulative distribution functions of the weighted mean of AETT were also plotted., Results: Childhood cancer patients could access the nearest hub hospital by traveling approximately 1.78 hours (AETT, range: 0.1 to 41.8) and 91.86 km (range: 1.0 to 1438.0). Moreover, a total of 94.5% of patients had the nearest hub hospital within their own regional block. The cumulative distribution functions of AETT indicated that many children in three blocks with multiple hub hospitals have shorter travel times and better hospital accessibility than those in other blocks., Conclusions: Although feasibility is ultimately dependent on each patient's condition and situation, child cancer patients on average can likely complete hospital visits from home and return within a single day. However, this is likely not the case for children who live at considerable distances from hub hospitals. We found regional differences in travel times and distances, depending on whether a given block contained multiple hub hospitals.

Although cancer metastasis is associated with poor prognosis, the mechanisms of this event, especially via lymphatic vessels, remain unclear. Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) is expressed on lymphatic vessel endothelium and is considered to be a specific marker of lymphatic vessels, but it is unknown how LYVE-1 is involved in the growth and metastasis of cancer cells. We produced rat monoclonal antibodies (mAb) recognizing the extracellular domain of mouse LYVE-1, and investigated the roles of LYVE-1 in tumor formation and metastasis. The mAb 38M and 64R were selected from hybridoma clones created by cell fusion between spleen cells of rats immunized with RH7777 rat hepatoma cells expressing green fluorescent protein (GFP)-fused mouse LYVE-1 proteins and mouse myeloma cells. Two mAb reacted with RH7777 and HEK293F human embryonic kidney cells expressing GFP-fused mouse LYVE-1 proteins in a GFP expression-dependent manner, and each recognized a distinct epitope. On immunohistology, the 38M mAb specifically stained lymphatic vessels in several mouse tissues. In the wound healing assay, the 64R mAb inhibited cell migration of HEK293F cells expressing LYVE-1 and mouse lymphatic endothelial cells (LEC), as well as tube formation by LEC. Furthermore, this mAb inhibited primary tumor formation and metastasis to lymph nodes in metastatic MDA-MB-231 xenograft models. This shows that LYVE-1 is involved in primary tumor formation and metastasis, and it may be a promising molecular target for cancer therapy., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: Lipiodol, which was used in transcatheter arterial chemoembolization before liver stereotactic body radiation therapy (SBRT), remains in SBRT. Previous we reported the dose enhancement in Lipiodol using 10 MV (10×) FFF beam. In this study, we compared the dose enhancement in Lipiodol and evaluated the probability of electron generation (PEG) for the dose enhancement using flattening filter (FF) and flattening filter free (FFF) beams., Methods: FF and FFF for 6 MV (6×) and 10× beams were delivered by TrueBeam. The dose enhancement factor (DEF), energy spectrum, and PEG was calculated using Monte Carlo (MC) code BEAMnrc and heavy ion transport code system (PHITS)., Results: DEFs for FF and FFF 6× beams were 7.0% and 17.0% at the center of Lipiodol (depth, 6.5 cm). DEFs for FF and FFF 10× beams were 8.2% and 10.5% at the center of Lipiodol. Spectral analysis revealed that the FFF beams contained more low-energy (0-0.3 MeV) electrons than the FF beams, and the FF beams contained more high-energy (>0.3 MeV) electrons than the FFF beams in Lipiodol. The difference between FFF and FF beam DEFs was larger for 6× than for 10×. This occurred because the 10× beams contained more high-energy electrons. The PEGs for photoelectric absorption and Compton scattering for the FFF beams were higher than those for the FF beams. The PEG for the photoelectric absorption was higher than that for Compton scattering., Conclusions: FFF beam contained more low-energy photons and it contributed to the dose enhancement. Energy spectra and PEGs are useful for analyzing the mechanisms of dose enhancement., (© 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)-6, a pleiotropic cytokine, is highly produced in the tumor-bearing host. Previous studies have indicated that IL-6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL-6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor-infiltrating CD11b + CD11c + cells isolated from colorectal cancer tissues showed strong induction of the IL-6 gene, downregulated surface expression of human leukocyte antigen (HLA)-DR, and an attenuated T cell-stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL-6-mediated STAT3 activation reduced surface expression of HLA-DR on CD14 + monocyte-derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL-6-mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL-6-mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL-6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: There are few recent data on trends in childhood cancer incidence using population-based cancer registries in Japan., Methods: This study comprised 6110 reported cases of patients aged 0-14 years who were diagnosed as having primary cancer between 1993 and 2009. We chose cancer registries of seven prefectures, according to the international cancer registry standard of fewer than 10% death certificate only cases among cancer registries in Japan. We analyzed population-based cancer registration data in the seven prefectures between 1993 and 2009. We calculated childhood cancer incidence, age-specific incidence, crude incidence rate, age-adjusted incidence rate, confidence intervals and annual change for each prefecture and classified the data into 12 diagnostic groups, according to the International Classification of Childhood Cancer (ICCC)., Results: According to sex-specific incidence, males accounted for slightly more cases than females. Children 0-3 years old accounted for 41.1% of patients. Leukemia accounted for 36.0% of cancers, followed by central nervous system tumors with 15.0%, according to the ICCC. The crude incidence rate did not change substantially, remaining at an average 8-11 per 100 000 population. In addition, the age-adjusted incidence rate remained constant with an average 2 per 100 000 population., Conclusions: Using population-based cancer registry data, age-specific incidence and 12 diagnostic groups according to the ICCC showed characteristics of childhood cancers. The incidence rate of childhood cancers has been nearly stable in Japan over the past 15 years., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Most patients suffering from cancer die of metastatic disease. Surgical removal of solid tumors is performed as an initial attempt to cure patients; however, surgery is often accompanied with trauma, which can promote early recurrence by provoking detachment of tumor cells into the blood stream or inducing systemic inflammation or both. We have previously reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduces inflammatory response and has a prophylactic effect on postoperative cardiopulmonary complications in lung cancer surgery. Here we demonstrate that cancer recurrence after curative surgery was significantly lower in ANP-treated patients than in control patients (surgery alone). ANP is known to bind specifically to NPR1 [also called guanylyl cyclase-A (GC-A) receptor]. In mouse models, we found that metastasis of GC-A-nonexpressing tumor cells (i.e., B16 mouse melanoma cells) to the lung was increased in vascular endothelium-specific GC-A knockout mice and decreased in vascular endothelium-specific GC-A transgenic mice compared with control mice. We examined the effect of ANP on tumor metastasis in mice treated with lipopolysaccharide, which mimics systemic inflammation induced by surgical stress. ANP inhibited the adhesion of cancer cells to pulmonary arterial and micro-vascular endothelial cells by suppressing the E-selectin expression that is promoted by inflammation. These results suggest that ANP prevents cancer metastasis by inhibiting the adhesion of tumor cells to inflamed endothelial cells.

Background: Despite the fact that rare cancer is a new target of cancer control in Japan, the incidence of rare cancers is unknown and there is no generally accepted definition of rare cancers in this country. With the aim of calculating incidences of rare cancers in Japan, we therefore adopted a definition and classification of rare cancers that had been published in the European Union (EU) in 2011., Methods: Using incidence data between 1998 and 2007 submitted by 12 of population based cancer registries in Japan that met our quality criteria and drawing on the EU definition (incidence <6 per 100,000 per year), we estimated the incidences of 845 combinations of tumor sites and histological groups and thus identified the cancers that are rare in Japan., Results: After identifying 193 combinations of tumor sites and histological groups that fit our criteria for rare cancers, we estimated their incidence to be about 75 per 100,000, which corresponds to about 94,800 new diagnoses in 2012 or approximately 15% of all cancer diagnoses. The categorization of rare and common cancers was almost the same in Japan as in EU., Conclusions: The present study provides an indication of the size of the rare cancer burden in Japan and epidemiological information to explore this. We are expecting further discussion based on our results with stakeholders in order to construct a Japanese definition of rare cancers., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Ketamine is often used to manage neuropathic pain in patients with cancer. However, it occasionally causes psychotomimetic effects such as vivid dreams, nightmares, illusions, hallucinations, and altered body image., Objective: To examine whether gradual dose titration of ketamine for management of neuropathic pain prevents psychotomimetic effects in patients with advanced cancer., Methods: This was a retrospective chart review. We administered ketamine when neuropathic pain in patients with advanced cancer became refractory to opioids and oral adjuvant analgesics. The starting dose of ketamine was 10 mg/d by continuous intravenous infusion. The dose was gradually increased by 10 mg/d every 4 to 6 hours to 50 mg/d or until the pain was relieved. It was subsequently increased by 25 mg/d every 12 to 24 hours until the pain was relieved., Results: For this study, we enrolled 46 patients with advanced cancer. The mean age was 52.2 ± 16.9 years. The mean dose at onset of action and maximum dose of ketamine were 56 ± 58 and 272 ± 214 mg/d, respectively. The mean pain intensity (numerical rating scale) decreased significantly from 7.3 ± 2.0 to 3.5 ± 2.2 after the administration of ketamine (P < .01). The effectiveness was 69.5%. No psychotomimetic effect of less than 300 mg/d was observed during the introduction phase even though psychotropic drugs were not prescribed. Mild sedation was observed in 3 patients (7%) as the only adverse effect during the introduction phase., Conclusion: Gradual dose titration of ketamine for management of neuropathic pain can prevent psychotomimetic effects in patients with advanced cancer.

Patients with cancer often experience insomnia. Nightmares are also a strong factor that interferes with the maintenance of comfortable and satisfying sleep. However, the prevalence and standard treatment of nightmares in patients with cancer have not been established yet. We aimed to treat insomnia and nightmares with trazodone. From 2008 to 2011, trazodone was prescribed to 30 patients with cancer who reported experiencing insomnia with or without nightmares to the palliative care team in Osaka University Hospital. Effective treatment was seen in 15 patients (50%). Four patients with cancer reported having severe nightmares and 2 patients had beneficial effects, with frightening dreams transformed into acceptable ones. Trazodone may be an effective drug for the treatment of insomnia and nightmares in patients with advanced cancer.

Background/aim: Oxidative stress in cancer patients has been demonstrated to be partly mediated by neutrophils. Although it is reported that natural antioxidants, such as green tea extract, reduce oxidative stress, there is limited evidence of their effects in cancer patients. This study aimed to determine the effect of green tea extract on reactive oxygen species produced by neutrophils from cancer patients., Materials and Methods: Peripheral blood samples were obtained from eighteen patients with advanced cancer. Green tea extract was added to the blood samples with luminol on Mebiol gel, and luminol-dependent chemiluminescence was measured to monitor the production of reactive oxygen species from migrated neutrophils into the gel, at 37°C., Results: Luminol-dependent chemiluminescence was significantly down-regulated in the presence of green tea extract in a concentration-dependent manner., Conclusion: These results indicate the antioxidant effect of green tea extract on reactive oxygen species produced by neutrophils, which may be effective in reducing oxidative stress in cancer patients.

Background: CD44 is a major cellular receptor for hyaluronic acids. The stem structure of CD44 encoded by ten normal exons can be enlarged by ten variant exons (v1-v10) by alternative splicing. We have succeeded in preparing MV5 fully human IgM and its class-switched GV5 IgG monoclonal antibody (mAb) recognizing the extracellular domain of a CD44R1 isoform that contains the inserted region coded by variant (v8, v9 and v10) exons and is expressed on the surface of various human epithelial cancer cells., Methods and Principal Findings: We demonstrated the growth inhibition of human cancer xenografts by a GV5 IgG mAb reshaped from an MV5 IgM. The epitope recognized by MV5 and GV5 was identified to a v8-coding region by the analysis of mAb binding to various recombinant CD44 proteins by enzyme-linked immunosorbent assay. GV5 showed preferential reactivity against various malignant human cells versus normal human cells assessed by flow cytometry and immunohistological analysis. When ME180 human uterine cervix carcinoma cells were subcutaneously inoculated to athymic mice with GV5, significant inhibition of tumor formation was observed. Furthermore, intraperitoneal injections of GV5markedly inhibited the growth of visible established tumors from HSC-3 human larynx carcinoma cells that had been subcutaneously transplanted one week before the first treatment with GV5. From in vitro experiments, antibody-dependent cellular cytotoxicity and internalization of CD44R1 seemed to be possible mechanisms for in vivo anti-tumor activity by GV5., Conclusions: CD44R1 is an excellent molecular target for mAb therapy of cancer, possibly superior to molecules targeted by existing therapeutic mAb, such as Trastuzumab and Cetuximab recognizing human epidermal growth factor receptor family.

Three kinds of survival rates are generally used depending on the purpose of the investigation: overall, cause-specific, and relative. The differences among these 3 survival rates are derived from their respective formulas; however, reports based on actual cancer registry data are few because of incomplete information and short follow-up duration recorded on cancer registration. The aim of this study was to numerically and visually compare these 3 survival rates on the basis of data from the Nagasaki Prefecture Cancer Registry. Subjects were patients diagnosed with cancer and registered in the registry between 1999 and 2003. We calculated the proportion of cause of death and 5-year survival rates. For lung, liver, or advanced stage cancers, the proportions of cancer-related death were high and the differences in survival rates were small. For prostate or early stage cancers, the proportions of death from other causes were high and the differences in survival rates were large. We concluded that the differences among the 3 survival rates increased when the proportion of death from other causes increased.

In previous studies we predicted future trends in cancer incidence for each prefecture in order to plan cancer control. Those predictions, however, did not take into account the characteristics of each prefecture. We therefore used the results of age-period-cohort analysis of incidence and mortality data of Osaka, and estimated the incidence and mortality of cancers at all sites and selected sites. The results reflect the characteristics of Osaka, which has and is expected to have large number of patients with liver cancer. We believe our results to be useful for planning and evaluating cancer control activities in Osaka. It would be worthwhile to base the estimation of cancer incidence and mortality in each prefecture on each population-based cancer registry.

L-type amino-acid transporter 1 (LAT1) is the first identified light chain of CD98 molecule, disulfide-linked to a heavy chain of CD98. Following cDNA cloning of chicken full-length LAT1, we have constructed targeting vectors for the disruption of chicken LAT1 gene from genomic DNA of chicken LAT1 consisting of 5.4kb. We established five homozygous LAT1-disrupted (LAT1(-/-)) cell clones, derived from a heterozygous LAT1(+/-) clone of DT40 chicken B cell line. Reactivity of anti-chicken CD98hc monoclonal antibody (mAb) with LAT1(-/-) DT40 cells was markedly decreased compared with that of wild-type DT40 cells. All LAT1(-/-) cells were deficient in L-type amino-acid transporting activity, although alternative-splice variant but not full-length mRNA of LAT1 was detected in these cells. LAT1(-/-) DT40 clones showed outstandingly slow growth in liquid culture and decreased colony-formation capacity in soft agar compared with wild-type DT40 cells. Cell-cycle analyses indicated that LAT1(-/-) DT40 clones have prolonged cell-cycle phases compared with wild-type or LAT1(+/-) DT40 cells. Knockdown of human LAT1 by small interfering RNAs resulted in marked in vitro cell-growth inhibition of human cancer cells, and in vivo tumor growth of HeLa cells in athymic mice was significantly inhibited by anti-human LAT1 mAb. All these results indicate essential roles of LAT1 in the cell proliferation and occurrence of malignant phenotypes and that LAT1 is a promising candidate as a molecular target of human cancer therapy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Appropriate use of anti-infective drugs is essential in clinical practice. No evidence-based guidelines or protocols have been published on the appropriate use of anti-infective drugs in patients receiving palliative care as yet., Methods: The medical records, which included the demographic data of patients, anti-infective drug use, bacteriologic findings, symptoms, and hematologic findings were reviewed retrospectively to determine the potential factors that contribute to symptom improvement of patients in terminal phase., Results: Seventy-one patients (64%) who received anti-infective drugs and had a total of 326 episodes of infection were assessed. Symptom improvement was seen in 33.1%. A total of 22.6% of episodes were started on anti-infective drugs during the last week of life and the symptom improvement in these episodes was 9.2%. Symptom improvement was hardly observed when the anti-infective drug was administered during the last week of life. The association between the decrease in the C-reactive protein (CRP) levels, the decrease of the leukocyte count, reduction of fever, and symptom improvement was determined. The decrease of CRP levels was 42.4%; leukocyte, 56.7%; and reduction of fever was 28.4%. The symptom improvement of individual treatment history was also investigated. The symptom improvement of the group who took positive treatment such as chemotherapy, radiotherapy, surgery, and catheter placement was significantly lower than that of no-treatment group., Conclusions: Active cancer treatment probably induces the symptoms related to infection and the use of anti-infective drugs. Unnecessary and excessive treatment should be avoided, and the symptoms should be managed with consideration of the patient's state of mind in order to improve the quality of life of terminally ill patients.

Cancer has been the primary cause of death in Japan for many years and accurate cancer incidence data are necessary in order to make plans for cancer control. Although population-based cancer registries are the best answer, regrettably there are still many regions with low accuracy registries. In an alternative estimation, cancer incidences have been analyzed by age-period-cohort (APC) models, allowing future prediction of cancer incidences in 2004. Considering the unexpectedly rapid aging of the Japanese population after this figure was reported, it would be worthwhile to examine more recent data. In this study, we therefore projected major cancer incidences based on the earlier results leaving estimated values for the age and cohort effects. Relating to the period effect, the most adequate scenario was selected from 12 projection methods. Furthermore, incidences when registration rates varied between 70 and 100% were calculated. As a result, different trends from reported incidences were observed for liver cancer in males, and trends of registration rates differed by sites. Until stable accurate registration data become available, it is difficult to judge whether predicted increase is real or only looks so because the registration rate is not 100%. However, it is clearly necessary to continuously observe variation in cancer incidences.

Background/aims: This study investigated the occurrence of malignancies in Japanese patients with Crohn's disease (CD) and compared the incidence with that in the general population., Methods: The medical records of 294 CD patients, treated between 1989 and 2009, were reviewed and the prevalence of malignancies was assessed. Registration of person-years at risk was calculated individually, from the year of CD diagnosis until the year of cancer diagnosis, death or end of follow-up. The observed number of cancer cases was compared with the expected number, calculated on the basis of the individually computed person-years at risk and the corresponding age- and sex-specific incidence rates in the background population., Results: Thirteen cancers developed in 12 patients among a total of 4,248 person-years available for analysis. There were six CRCs, two gastric cancers, two uterine cancers, one small bowel cancer, one biliary cancer, and one cancer of unknown primary site. The risk of cancer (all sites) was significantly increased from that of the background population; SIR 2.24 (95% CI 1.19-3.83). In particular, the risk of CRC significantly increased in comparison to that of the background population; SIR 5.80 (95% CI 2.13-12.68)., Conclusions: Japanese patients with CD are at increased risk of cancer, particularly CRC.

In medical care systems for cancer, it is important to consider the issues of standardization and centralization. In this study, we employed the Nagasaki Cancer Registry, which has a high registry rate, to investigate standardization and centralization for five major cancers, in addition to childhood malignancies (which are often rare types). Subjects were patients diagnosed with cancer and registered in the Nagasaki Cancer Registry between 1985 and 2004. For standardization, we calculated a Preference Index and five-year survival rate, and for centralization we investigated Pareto curves and Gini coefficients as well as the annual average number of cases per hospital. Results suggested that patients migrate to medical service areas different from where they reside in order to receive treatment at facilities thought to have a better record of treatment. In addition, while the number of patients and treatment facilities for childhood cancer was decreasing due to a decline in the number of children, the centralized tendency differed for the 12 diagnoses assessed. By conducting analyses based on population-based cancer registries using the evaluation methods employed in this study, it should be possible to investigate patients' migrant patterns, as well as to develop systems for providing medical care in secondary medical service areas.

In this paper, we describe the methodology of the case and control selection for the first-wave nested case-control study within the JACC Study. Among the subjects participating in the cohort, serum samples of 42,249 subjects (including 39,242 subjects aged between 40 and 79 at the baseline) were suitable for biochemical analysis. We here selected those who had died by 1997 or who were diagnosed with cancer with sera until 1994 as cases. For each case, 3 to 4 controls with sera were randomly selected, with matching for gender, age (as near as possible) and residential area. As a result, 3,144 cases and 10,661 controls (2,867 cases and 10,351 controls were 40 to 79 years old at the baseline) were selected to measure serum IGF-I, IGF-II, IGFBP-3, TGF-b1 and sFas values and total SOD activity. Cases were older and more likely to be men than the JACC Study subjects. Moreover, they were much older than controls because of the age-dependence of susceptibility to death, especially among men. There were more smokers among cases compared with controls, though drinkers at the baseline were fewer. Among deceased cases, cancer was the leading cause of death, followed by cardiovascular diseases. Lung cancer was most frequent among deceased cancer cases and the next most common site was the stomach. The leading cause of cancer incidence was stomach cancer followed by lung cancer. Simple comparison of means and distribution of IGF-I, IGF-II, IGFBP-3, TGF-b1, sFas and total SOD activity between cases and controls revealed total SOD activity and sFas levels of cases to be higher than controls, while for the other components the opposite was found.

Vitamin C (ascorbic acid, ascorbate) has a controversial history in cancer treatment. Emerging evidence indicates that ascorbate in cancer treatment deserves re-examination. As research results concerning ascorbate pharmacokinetics and its mechanisms of action against tumor cells have been published, and as evidence from case studies has continued to mount that ascorbate therapy could be effective if the right protocols were used, interest among physicians and scientists has increased. In this review, high-dose vitamin C therapy in cancer treatment is re-evaluated.

Objective: To analyze the tendency to centralize childhood cancer treatment among cancer treatment hospitals in Osaka, Japan over a 28-year period., Methods: The subjects were patients under the age of 15, newly diagnosed with cancer in Osaka between 1975 and 2002 (n = 4738). They were categorized into three groups by the time diagnosed (1975-84, 1985-93 and 1994-2002). The International Classification of Childhood Cancer was used as the disease classification. The degree of centralization was examined using a Pareto analysis, the Gini coefficient and the annual average number of cases per hospital., Results: During this period, the number of children with cancer in Osaka has decreased by nearly half, from 2.1 to 1.2 million and the number of hospitals treating childhood cancer decreased from 37 to 20. However, the Pareto curve and Gini coefficient were almost constant (0.747, 0.737, 0.756 in Gini coefficient for the three diagnosed periods). The annual average numbers of cases per hospital were much low and marginally increased from 5.6 during 1975-84 to 6.1 during 1994-2002 in the hospitals that treated 90% of all cancers., Conclusions: The degree of centralization appeared to be almost constant from 1975 to 2002 regardless of the decrease in hospitals treating cancer patients.

Objective: Hospital-based cancer registry involves complex processing steps that span across multiple departments. In addition, management techniques and registration procedures differ depending on each medical facility. Establishing processes for hospital-based cancer registry requires clarifying specific functions and labor needed. In recent years, the business modeling technique, in which management evaluation is done by clearly spelling out processes and functions, has been applied to business process analysis. However, there are few analytical reports describing the applications of these concepts to medical-related work. In this study, we initially sought to model hospital-based cancer registration processes using the Unified Modeling Language (UML), to clarify functions., Methods: The object of this study was the cancer registry of Osaka University Hospital. We organized the hospital-based cancer registration processes based on interview and observational surveys, and produced an As-Is model using activity, use-case, and class diagrams. After drafting every UML model, it was fed-back to practitioners to check its validity and improved., Results: We were able to define the workflow for each department using activity diagrams. In addition, by using use-case diagrams we were able to classify each department within the hospital as a system, and thereby specify the core processes and staff that were responsible for each department. The class diagrams were effective in systematically organizing the information to be used for hospital-based cancer registries. Using UML modeling, hospital-based cancer registration processes were broadly classified into three separate processes, namely, registration tasks, quality control, and filing data. An additional 14 functions were also extracted. Many tasks take place within the hospital-based cancer registry office, but the process of providing information spans across multiple departments. Moreover, additional tasks were required in comparison to using a standardized system because the hospital-based cancer registration system was constructed with the pre-existing computer system in Osaka University Hospital. Difficulty of utilization of useful information for cancer registration processes was shown to increase the task workload., Conclusion: By using UML, we were able to clarify functions and extract the typical processes for a hospital-based cancer registry. Modeling can provide a basis of process analysis for establishment of efficient hospital-based cancer registration processes in each institute.

Measuring cancer prevalence in Japan has been difficult because population-based cancer registries have been conducted in limited areas. The purpose of this study was to estimate cancer prevalence in Japan from 1995 to 2020 for 5-year periods based on selected population-based cancer registry data. 1-, 2-3-, 4-5- and 5-year partial prevalence were estimated using incidence and survival data. Incidence and survival were calculated using data from selected cancer registries. We estimated the cancer survival by age group, primary site, and sex using the mixture cure fraction model. Kaplan-Meier estimates were applied to subgroups for which the survival did not converge to the estimated model. We projected that 1-year cancer prevalence for all sites would increase from 209 971 to 367 354 for men and from 164 622 to 275 776 for women, that 2-3-year prevalence would increase from 288 284 to 508 731 for men and from 255 684 to 418 630 for women, that 4-5-year prevalence would increase from 216 834 to 379 461 in men and from 211 764 to 342 031 in women, and that 5-year prevalence would increase from 715 089 to 1 255 546 in men and from 632 070 to 1 036 437 in women. This study is the first estimate of cancer prevalence in the future in Japan.

Background: Five-year survival is an important index for evaluating the overall effectiveness of cancer diagnosis and treatment. The aim of this study was to monitor trends in 5-year cancer survival in Osaka, Japan, during 1975-94, with adjustment for trends in age and stage at diagnosis., Methods: Five-year crude survival was estimated for cancers of the stomach (39,697 patients), lung (17,400 patients) and breast (11,988 women) in four consecutive 5-year periods, with adjustment for age and/or stage, using the age and stage distribution of cases diagnosed during 1975-79 as standard weights. We estimated the impact of adjusting for either age or stage alone by their proportionate impact on the trend in fully (age- and stage-) adjusted survival., Results: The absolute increase in unadjusted 5-year survival over 20 years was about 20% for stomach cancer, 14% for breast cancer and 5% for lung cancer. Lack of age adjustment would have caused proportionate under-estimation of these trends by 13-14% (stomach), 7% (breast), 14% (lung, men) and 4% (lung, women). Lack of adjustment for the trend toward earlier stage would have caused proportionate over-estimation (152%, men: 133%, women) of stomach cancer survival trends, which seemed more influenced by earlier diagnosis than more effective treatment. For breast cancer, the 31% over-estimation of trend from lack of stage adjustment suggests the impact of earlier diagnosis, while the improvement of survival after additional adjustment for age may be due to more effective treatment. Failure to adjust for stage led to a proportionate 21% under-estimation of lung cancer survival trends for men, and 4% over-estimation for women., Conclusion: This study confirms the importance of adjusting for trends in age and stage distribution when evaluating time trends in cancer survival.

Macrophages are predominantly involved in the immune and inflammatory processes of solid tumors. Macrophages infiltrated into a tumor have an ambivalent relationship with the tumor, because they are innately very flexible and adaptable depending on the microenvironment of the tissue and the tissue-derived factors. The relationship between tumor-associated macrophages (TAMs) and a tumor is extremely complicated and has not yet been clearly elucidated. Now, the reintegration of biological knowledge including immunology, pathology and oncology is indispensable for the clinical application of TAMs to cancer therapy. In this review, we focus on the range of pro- and anti-tumor functions performed by TAMs and outline a new class of cancer therapies that aims at controlling the complex functions of TAMs.

Background: Quality assurance (QA) of clinical practice is important for any medical specialty. Programs based on the Patterns of Care Study (PCS) have been developed to compare the quality of radiotherapeutic care at individual institutions, with the national average representing the process and outcome of radiotherapy. The feasibility of these programs was analyzed., Methods: Calculation programs for the national average and standard score were developed to evaluate quantitatively the process and outcome of radiotherapy at individual institutions as well as at the national level. The programs were used to evaluate the quality of radiotherapy for 561 esophageal carcinoma patients surveyed in the Japanese PCS., Results: As a representative example of QA measurement, the national average for the 5-year survival rate for these patients in the nonsurgery group was 5%. The regional averages for those in academic and nonacademic institutions were 9% and 1%, respectively (P = 0.0142), showing a significant difference between these two institutional strata. The standard score compared with the national average for institution No.105, for example, was 16.3 (P < 0.0001), with the positive value indicating that the outcome at this institution was significantly higher than the national average. The corresponding figure compared with the regional average was -0.3 (P = 0.7391), with the negative value indicating the outcome is not superior to the regional average of academic institutions., Conclusions: These programs make it possible to compare quantitatively the quality of radiation therapy at individual institutions with the national and regional averages. They should also be useful for nationwide QA projects in radiation oncology as well as in other medical specialities., (Copyright 2002 American Cancer Society.)

The Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study) included in its self-administered questionnaires some single-item questions concerning physical activity. We examined the validity of the questions among 1,730 Japanese adults and the reliability of the questions among 1,075 Japanese adults. The validity of the sports and physical exercise questions was estimated by comparing the self-administered questionnaire responses with the time spent on the activity and the energy expenditure index for the previous 12-month period, elicited by the interviewing method used in the Japan Lifestyle Monitoring Study with a minor modification. The Spearman's rank correlation coefficients ranged from 0.43 to 0.60, showing moderate correlations. On the other hand, test-retest reliability was estimated by comparing the responses from two separate surveys conducted roughly one year apart. Weighted kappa coefficients of sports and physical exercise questions, classified according to sex and age, ranged from 0.39 to 0.56, showing moderate reliability; and those of a question about walking ranged from 0.25 to 0.39, showing fair reliability. We suggest that measuring physical activity level with these single-item questions may be appropriate for establishing baseline data that reflects long-term physical activity in a large-scale cohort study targeting lifestyle-related diseases.

This paper primarily aimed to overview the rationale for initiating the Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (Ministry of Education, Science, Sports and Culture of Japan) (JACC Study), by comparing socio-demographic and nutritional changes that were witnessed between 1965 and 1990 in Japan, and also to describe the study design, the follow-up conditions as of the end of 1997, and the frameworks for analyzing the data of the lung, stomach, pancreas and gallbladder/bile duct, based on the approximately 8-year follow-up data. For other major sites such as cancers of the large intestine and liver, an analysis will be started in the fiscal year of 2002. This paper secondarily aimed to be cited as the basic information on the JACC Study when several publications are to be based on.

Background: Recently, as the number of elderly people in Japan is growing, so is the number of new cancer cases. The number of patients treated with radiotherapy is therefore also on the increase, so that it is important to estimate the future demand for radiotherapy and to make preparations for it., Methods: All the surveys were conducted for 106 facilities selected randomly out of 556 radiotherapy facilities in Japan. To obtain trends in the number of new cancer patients treated with radiotherapy in Japan, we conducted a survey with a self-administered mail questionnaire designed to obtain the number of new patients treated with radiotherapy for each year of the past decade (1990-99). The future number of new patients treated with radiotherapy was estimated from the data thus obtained. To investigate structural problems of Japanese radiotherapy, surveys about the number of treatment machines and full-time equivalent (FTE) radiation oncologists were conducted according to data from the Japanese Society for Therapeutic Radiology and Oncology (JASTRO) structure survey and the Patterns of Care Study (PCS). We also compared the structure of Japanese radiotherapy with that in the USA., Results: The number of patients treated with radiotherapy has increased for every institutional stratum, with an overall increase of 1.4-fold over the past 10 years in Japan. It is estimated that the number of cancer patients treated with radiotherapy will reach 190 000 in 2015. In Japanese non-academic institutions, less than one FTE radiation oncologist has been managing many of these patients. In both equipment and manpower, academic institutions exceed nonacademic institutions., Conclusion: The future demand for Japanese radiotherapy will grow substantially, so that it is of vital importance to prepare for it. Specifically, the number of FTE radiation oncologists must be increased.

The clinical quality assurance (QA) of an institution is important in any multiinstitutional prospective study. Patterns of Care Study (PCS) is a well-known study for QA activity in the United States. PCS is a nationwide retrospective study done by two-staged cluster sampling of institutions and patients and external audits. After data are accumulated, National averages on various survey items are calculated as a QA measure. In 1996, PCS was imported into the radiation oncology field in Japan with the support of the Ministry of Health and Welfare. Preliminary results showed significant differences in treatment process, structure, and preliminary outcome according to the stratification of institutions. These data can be useful in improving the structure and process at the institutional as well as the national level. PCS will also clarify the dissemination of positive clinical results into national practice.

Epidemiological studies which examine an association between low serum cholesterol level and cancer risk of all sites were reviewed and a summary of major findings are as follows: (1) In most reports, low serum cholesterol level, which associated with cancer of all sites, cancer deaths/incidence occurred within a few years after cholesterol measurement were performed. This short-term association is believed to be a preclinical cancer effect, i.e., preclinical cancer itself reduces serum cholesterol level. (2) A long-term inverse association between serum cholesterol and cancer risk of all sites was observed in some studies. This association cannot be explained by either a preclinical cancer effect or by chance. The epidemiological implications of this association was discussed in depth. (3) A long-term inverse association between serum cholesterol level and cancer mortality/incidence was observed mainly in men, but not in women. In a few studies which reported an inverse association in women, follow-up periods were rather short. (4) A few epidemiological studies conducted in Japan also detected a long-term inverse relationship between serum cholesterol level and cancer risk of all sites in men, but not in women. Since low serum cholesterol level may possibly be a risk factor for cancer of all sites, further investigation involving experimental studies on animals and longitudinal population-based study appear to be necessary for confirmation of this factor.

Spontaneous tumors in 296 male and 297 female F-34/DuCrj rats used as control groups in six carcinogenicity tests were tabulated and evaluated. In males the most frequent tumors were testicular interstitial cell tumors, followed by mammary fibromas and fibroadenomas, mononuclear cell leukemias, pheochromocytomas, C-cell adenomas of the thyroid, pituitary adenomas, preputial adenomas, neoplastic nodules of the liver, and lung adenomas. In contrast, in females pituitary adenomas, uterine endometrial stromal polyps, mammary fibroadenomas, mononuclear cell leukemias and C-cell adenomas were the most common. Various other tumors of almost all other organs and/or tissues were found, although their incidences were low. Variability in the rates of incidence in some tumors was observed in different control groups.

The carcinogenicity of sodium and of sodium nitrate was examined in F-344 rats. Sodium nitrite was administered in the drinking-water for 2 yr at levels of 0.125 or 0.25%. Sodium nitrate was given in the diet at levels 2.5 or 5%. A variety of tumours occurred in all groups including the controls. The only significant difference between treated and control groups in the total number of tumours detected in either of the studies was a significant decrease in tumour incidence in the high-dose females given nitrite compared with controls. There was no positive dose-response relationship either in the incidence or in the induction time of tumours in either of the studies. The only significant result was a reduction in the incidence of mononuclear cell leukaemias in the experimental groups in both studies. It is concluded that sodium nitrite and sodium nitrate did not exert a carcinogenic effect that could be detected under the conditions of this study in which the animals showed a high incidence of spontaneous tumours.

We examined the contribution of host factors in carcinogenesis by evaluating the frequency distributions and secular trends in available epidemiologic data of mortality and morbidity around the world. In most developed countries, the age-adjusted death rates of cancer of all sites have levelled off in recent years and the intercountry difference in mortality is small. Deaths from cancer account for approximately 20% of total deaths in these countries. It is believed that the difference in cancer mortality of all sites between the developed and developing countries can be explained by the different levels of mortality from infectious and parasitic diseases, including deaths from tuberculosis. A certain upper limit for the number of cancer deaths in each population is strongly suggested by the unaltered cumulative mortality rate from cancer and tuberculosis up to 85 years of age in a defined birth cohort in the developed countries. The apparent age dependency in cancer mortality as well as some other essential epidemiologic implications in carcinogenesis, the commonly observed proportion of cancer deaths of around 20% of total deaths, and the well-known etiologic importance of environmental factors which determines the site-specific cancer mortality and morbidity lead one to consider the definite existence of "susceptibles to cancer" in each population. However, the concept of susceptibles to cancer is different from the usual one of hereditary predisposition to so-called "intractable diseases," which have low incidence rates.

The geographic pattern of disease has been visually studied by depicting the categorized mortality or morbidity rates on a map. Visual study, however, by no means indicates the statistical significance of observed clusters, i.e., whether or not the geographic aggregations could occur by chance alone. In this paper, an approach for assessing the deviation from chance expectation of the geographic pattern actually observed on the map is described. A simple chi-square test is proposed, and its validity is substantiated by a Monte Carlo approach, which is derived analytically as a special case of Knox's test for space--time clustering. The parameters required for the test are (1) total number of areas, (2) numbers of subareas for each mortality of morbidity category, (3) total number of geographically adjacent areas, and (4) observed numbers of adjacent areas having concordant category pairs.