Search

Background: Cancer patients are more susceptible to an aggressive course of COVID-19. Developing biomarkers identifying cancer patients at high risk of COVID-19-related death could help determine who needs early clinical intervention. The miRNAs hosted in the genomic regions associated with the risk of aggressive COVID-19 could represent potential biomarkers for clinical outcomes., Patients and Methods: Plasma samples were collected at The University of Texas MD Anderson Cancer Center from cancer patients (N = 128) affected by COVID-19. Serum samples were collected from vaccinated healthy individuals (n = 23) at the Municipal Clinical Emergency Teaching Hospital in Timisoara, Romania. An in silico positional cloning approach was used to identify the presence of miRNAs at COVID-19 risk-associated genomic regions: CORSAIRs (COvid-19 RiSk AssocIated genomic Regions). The miRNA levels were measured by RT-qPCR., Results: We found that miRNAs were enriched in CORSAIR. Low plasma levels of hsa-miR-150-5p and hsa-miR-93-5p were associated with higher COVID-19-related death. The levels of hsa-miR-92b-3p were associated with SARS-CoV-2 test positivity. Peripheral blood mononuclear cells (PBMC) increased secretion of hsa-miR-150-5p, hsa-miR-93-5p, and hsa-miR-92b-3p after in vitro TLR7/8- and T cell receptor (TCR)-mediated activation. Increased levels of these three miRNAs were measured in the serum samples of healthy individuals between one and nine months after the second dose of the Pfizer-BioNTech COVID-19 vaccine. SARS-CoV-2 infection of human airway epithelial cells influenced the miRNA levels inside their secreted extracellular vesicles., Conclusions: MiRNAs are enriched at CORSAIR. Plasma miRNA levels can represent a potential blood biomarker for predicting COVID-19-related death in cancer patients., (© 2024. The Author(s).)

Purpose: In this study, we aimed to evaluate the safety and effectiveness of naldemedine for treating opioid-induced constipation (OIC) in patients with advanced cancer, who are receiving palliative care, and particularly explored its early effects., Methods: Palliative care teams and inpatient palliative care units across 14 institutions in Japan were included in this multicenter, prospective, observational study. Patients who were newly prescribed a daily oral dose of 0.2 mg naldemedine were enrolled. The spontaneous bowel movement (SBM) within 24 h after the first dose of naldemedine was considered the primary outcome, whereas, the secondary outcomes included weekly changes in SBM frequency and adverse events., Results: A total of 204 patients were enrolled and 184 completed the 7-day study. The average age of the participants (103 males, 101 females) was 63 ± 14 years. The primary cancer was detected in the lungs (23.5%), gastrointestinal tract (13.7%), and urological organs (9.3%). A considerable proportion of patients (34.8%) had ECOG performance status of 3-4. Most patients were undergoing active cancer treatment, however, 40.7% of the patients were receiving the best supportive care. Within 24 h of the first naldemedine dose, 146 patients (71.6%, 95% CI: 65.4-77.8%) experienced SBMs. The weekly SBM counts increased in 62.7% of the participants. The major adverse events included diarrhea and abdominal pain, detected in 17.6% and 5.4% of the patients, respectively. However, no serious adverse events were observed., Conclusion: Conclusively, naldemedine is effective and safe for OIC treatments in real-world palliative care settings., Trial Registration Number: UMIN000031381, registered 20/02/2018., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Malnutrition in children with cancer is associated with poor prognosis. This study aimed to determine whether nutritional support team (NST) interventions prevent adverse events and improve the nutritional status in pediatric patients admitted for cancer treatment. This was a historical cohort study of pediatric patients with acute lymphocytic leukemia, acute myeloid leukemia, neuroblastoma, or brain tumor who received chemotherapy or underwent hematopoietic stem cell transplantation. Patients admitted between June 2013 and October 2014 were classified into the intervention group. Those admitted between January 2011 and December 2012 were classified into the control group. We created a homogeneous probability model using the inverse probability of treatment weighting method, and compared outcomes. A total of 75 patients were included in the study (38 and 37 in the intervention and control groups, respectively). The intervention group had significantly fewer incidents of nothing by mouth (nil per os [NPO]) (p=0.037) and days of NPO (p=0.046) than the control group. There was no significant difference between the intervention and control groups regarding the change in body mass index z-score between admission and discharge (p=0.376). NST interventions for children with cancer were associated with a reduction in the number of NPO occurrences and NPO days. These findings suggest that NST interventions contribute to continued oral intake.

Context: Cancer pain is a common complication that is frequently undertreated in patients with cancer., Objectives: This study is aimed at assessing the time needed to achieve cancer pain management goals through specialized palliative care (SPC)., Methods: This was a multicenter, prospective, longitudinal study of inpatients with cancer pain who received SPC. Patients were continuously followed up until they considered cancer pain management successful, and we estimated this duration using the Kaplan-Meier method. We investigated the effectiveness of pain management using multiple patient-reported outcomes (PROs) and quantitative measures, including pain intensity change in the Brief Pain Inventory. A paired-sample t-test was used to compare the pain intensity at the beginning and end of the observation period., Results: Cancer pain management based on the PROs was achieved in 87.9% (385/438) of all cases. In 94.5% (364/385) of these cases, cancer pain management was achieved within 1 week, and the median time to pain management was 3 days (95% confidence interval [CI], 2-3). The mean worst pain intensity in the last 24 h at the start and end of observation were 6.9 ± 2.2 and 4.0 ± 2.3, respectively, with a difference of -2.9 (95% CI, -3.2 to -2.6; p < 0.01). Overall, 81.6% of the patients reported satisfaction with cancer pain management, and 62 adverse events occurred., Conclusion: SPC achieved cancer pain management over a short period with a high level of patient satisfaction resulting in significant pain reduction and few documented adverse events., (Copyright © 2023 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: One primary concern about receiving care at home is that survival might be shortened because the quality and quantity of treatment provided at home will be inferior to that given in the hospital. Although our previous study demonstrated a longer survival of those with home-based palliative care (PC), it lacked adjustment for some potential confounders including symptoms and treatments during the stay. We aimed to compare the survival times among advanced cancer patients receiving home-based and hospital-based PC with adjusting for symptoms and treatments., Method: We compared survival time of participants who enrolled two multicenter, prospective cohort studies of advanced cancer patients at 45-home-based PC services between July 2017 and December 2017, and at 23-hospital-based PC services between January 2017 and December 2017. We analyzed with stratification by the estimated survival of Days, Weeks, and Months, which were defined by modified Prognosis in Palliative care Study predictor models-A. We conducted a Cox regression analysis with adjusting for potential confounders including symptoms and treatments during the stay., Results: A total of 2,998 patients were enrolled in both studies and 2,878 patients were analyzed; 988 patients receiving home-based PC and 1,890 receiving hospital-based PC. The survival time of patients receiving home-based PC was significantly longer than that of patients receiving hospital-based PC for the Days Prognosis (estimated median survival time: 10 days [95% CI 8.1-11.8] vs. 9 days [95% CI 8.3-10.4], p = 0.157), the Weeks prognosis (32 days [95% CI 28.9-35.4] vs. 22 days [95% CI 20.3-22.9], p < 0.001), and the Months Prognosis, (65 days [95% CI 58.2-73.2] vs. 32 days [95% CI 28.9-35.4], p < 0.001)., Conclusion: In this cohort of advanced cancer patients with a Weeks or Months prognosis, those receiving home-based PC survived longer than those receiving hospital-based PC after adjusting for symptoms and treatments., Competing Interests: None of the authors have any financial or personal relationships to declare., (Copyright: © 2023 Hamano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The spatially organized gene expression program within the liver specifies hepatocyte functions according to their relative distances to the bloodstream (i.e., zonation), contributing to liver homeostasis. Despite the knowledge that solid cancers remotely disrupt liver homeostasis, it remains unexplored whether solid cancers affect liver zonation. Here, using spatial transcriptomics, we thoroughly investigate the abundance and zonation of hepatic genes in cancer-bearing mice. We find that breast cancers affect liver zonation in various distinct manners depending on biological pathways. Aspartate metabolism and triglyceride catabolic processes retain relatively intact zonation patterns, but the zonation of xenobiotic catabolic process genes exhibits a strong disruption. The acute phase response is induced in zonated manners. Furthermore, we demonstrate that breast cancers activate innate immune cells in particular neutrophils in distinct zonated manners, rather than in a uniform fashion within the liver. Collectively, breast cancers disorganize hepatic transcriptomes in zonated manners, thereby disrupting zonated functions of the liver., (© 2023. The Author(s).)

Introduction/objectives: There is growing consensus on the benefits of initiating palliative care early in the disease trajectory; however, palliative care needs for non-cancer patients remain to be elucidated. We investigated the trajectory of unresolved palliative care needs of non-cancer patients at home and explored associated factors., Methods: We conducted a multicenter prospective cohort study of elderly non-cancer patients at home in Japan between Jan 2020 and Dec 2020. Physicians assessed their palliative care needs using the Integrated Palliative Care Outcome Scale (IPOS). Unresolved palliative care needs were defined as IPOS symptoms above 2 (moderate)., Results: In total, 785 patients were enrolled. The most frequent unresolved palliative care needs at enrollment were poor mobility (n = 438, 55.8%), followed by weakness/lack of energy (n = 181, 23.1%) and poor appetite (n = 160, 20.4%). Multivariate logistic regression analysis revealed that female and musculoskeletal disease were significantly positively associated with pain at starting home visits (OR = 1.89, P  = .015; OR = 2.69, P  = .005). In addition, neurological diseases were significantly positively associated with constipation and poor mobility 3 months after starting home visits (OR = 3.75, P  = .047; OR = 3.04, P  = .009)., Conclusions: The order of the prevalence of unresolved palliative care needs may remain relatively stable over time, even for those receiving home-based palliative care services. We identified several specific diseases and conditions that were significantly associated with unresolved palliative care needs., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Opioid-induced constipation (OIC) is one of the most common adverse events of opioid therapy and can severely reduce quality of life (QOL). Naldemedine is the orally available peripheral-acting μ-opioid receptor antagonist approved for OIC treatment. However in daily clinical practice, some cancer patients show insufficient control of OIC even while receiving naldemedine., Objective: To identify factors associated with non-response to naldemedine in cancer patients., Methods: This study retrospectively analyzed 127 cancer patients prescribed naldemedine at Seirei Hamamatsu General Hospital in Japan between November 2016 and June 2021. For the regression analysis of factors associated with OIC, variables were extracted manually from electronic medical records. Naldemedine had been prescribed by the attending physician after the presence of OIC had been defined with reference to Rome IV diagnostic criteria. Naldemedine was evaluated as "effective" in cases where the number of defecations increased at least once in the first 3 days after starting naldemedine. Multivariate logistic regression analysis was performed to identify factors associated with non-response to naldemedine. The data used were from the group of patients who received naldemedine in our previous study., Results: Factors significantly associated with non-response to naldemedine included chemotherapy with taxanes within 1 month of evaluation of naldemedine effect (odds ratio [OR] = 0.063; 95% confidence interval [CI] = 0.007-0.568), and addition of or switching to naldemedine due to insufficient efficacy of prior laxatives (OR = 0.352, 95% CI = 0.129-0.966)., Conclusion: The identification of factors associated with non-response to naldemedine prescribed for OIC may help improve QOL among cancer patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Kanbayashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: This study aimed to analyze and categorize the actual situation of employment consultation and support according to consultation times or employment status at the Consultation Support Center of the National Cancer Center Hospital of Japan., Methods: We retrospectively analyzed the patient backgrounds, consultation contents, and the number of employment consultation cases conducted at the Consultation Support Center of the National Cancer Center Hospital during a 6-month period from May to December 2018., Results: During the study period, 117 patients (male: female = 46:71) visited the Consultation Support Center. The median age of patients was 48 years old. The most common primary cancer site was the breast in 28 patients followed by the lung in 16 patients, and then gynecologic cancer in 10 patients. The most common cancer treatment was chemotherapy in 53 patients (45.3%), and 12 patients (10.2%) were recurrent patients. Fifty-two patients were in regular employment, 24 were unemployed, 17 were of unknown employment status, 16 were in non-regular employment, and 8 were classified/categorized as other. In terms of working status, 40 were on leave, 35 were working, 15 were seeking work, 8 were unemployed, and 19 were categorized as other. The median number of consultations was 1 (1,11). The content of consultations was the social security system in 44 cases (37.6%) job seeking in 24 cases (20.5%), how to inform the workplace in 14 cases (12%), and workplace environment adjustment in 13 cases (11.1%)., Conclusions: We conducted a survey on the actual status of employment consultation in a cancer center hospital. The majority of consultations were completed in one session. In terms of the content of consultations, there was a high need for consultations on the social security system and job seeking. Further study is needed on the characteristics of employment consultations according to employment status and other attributes.

Purpose: To identify risk factors for opioid-induced constipation (OIC)., Methods: This study retrospectively analyzed 175 advanced cancer patients who were receiving pain treatment with opioids and were newly prescribed laxatives for OIC at Seirei Hamamatsu General Hospital between November 2016 and June 2021. For the regression analysis of factors associated with OIC, variables were extracted manually from clinical records. The effect of newly prescribed laxatives for OIC was evaluated as "effective" in cases where the number of spontaneous bowel movements increased at least once in the first 3 days. The OIC was defined based on Rome IV diagnostic criteria. Multivariate logistic regression analysis was performed to identify risk factors for OIC. Optimal cutoff thresholds were determined using receiver operating characteristic analysis. Values of P < 0.05 (two-tailed) were considered significant., Results: Significant factors identified included body mass index (BMI) (odds ratio [OR] = 0.141, 95% confidence interval [CI] = 0.027-0.733; P = 0.020), chemotherapy with taxane within 1 month of evaluation of laxative effect (OR = 0.255, 95% CI = 0.068-0.958; P = 0.043), use of naldemedine (OR = 2.791, 95% CI = 1.220-6.385; P = 0.015), and addition or switching due to insufficient prior laxatives (OR = 0.339, 95% CI = 0.143-0.800; P = 0.014)., Conclusion: High BMI, chemotherapy including a taxane within 1 month of evaluation of laxative effect, no use of naldemedine, and addition or switching due to insufficient prior laxatives were identified as risk factors for OIC in advanced cancer patients with cancer pain., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To evaluate the quality of the structure and process of cancer care from the perspective of patients with cancer, we developed a Cancer Care Evaluation Scale., Methods: Two anonymous online surveys of patients with cancer in Japan were conducted using a convenience sample of 400 adult cancer outpatients., Results: In total, 162 patients participated in the online surveys. Factor analysis revealed that the Cancer Care Evaluation Scale had the following 12 domains: (i) relationship with physician, (ii) relationship with nurse, (iii) physical care by physician, (iv) physical care by nurse, (v) psycho-existential care, (vi) help with decision-making for patients, (vii) coordination and consistency, (viii) environment, (ix) cost, (x) availability, (xi) care for the side effects of cancer treatment by a physician, and (xii) care for the side effects of cancer treatment by a nurse. The Cancer Care Evaluation Scale was correlated with overall care satisfaction (r = 0.75), but not with the quality of life (r = 0.40). In regard to rest-retest reliability, most items showed an intraclass correlation coefficient of 0.7 or higher., Conclusion: The validity and reliability of the Cancer Care Evaluation Scale were confirmed, suggesting that this tool is useful for evaluating the quality of cancer care from the perspective of patients with cancer., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Human lactoferrin (hLF), a soluble factor of the innate immune system, exhibits various biological functions and therefore has potential as a therapeutic protein. However, the clinical applications of hLF are limited by its low stability in blood. We therefore attempted to resolve this by producing recombinant hLF fused to human serum albumin (HSA). Two HSA-fused hLFs with different fusion orientations (hLF-HSA and HSA-hLF) were produced in Chinese hamster ovary (CHO) DG44 cells. hLF-HSA revealed higher thermal stability, resistance to peptic degradation, and stability during the process of cellular uptake and release in an intestinal enterocyte model (Caco-2 cells) than HSA-hLF. The lower stability of HSA-hLF is presumably due to the steric hindrance imposed by HSA fusion to the N-terminus of hLF. Both HSA fusion proteins, especially HSA-hLF, displayed improved pharmacokinetic properties despite the lower protein stability of HSA-hLF. hLF-HSA and HSA-hLF exhibited approximately 3.3- and 20.7-fold longer half-lives (64.0 and 403.6 min), respectively, than holo-rhLF (19.5 min). Both HSA fusion proteins were found to exert enhanced growth inhibition effects on cancer cells in vitro, but not normal cells. Their enhanced growth inhibitory activities were considered to be due to the synergetic effects of hLF and HSA because hLF alone or HSA alone failed to exert such an effect. Altogether, Fusion of HSA to hLF yielded superior pharmacokinetics and anti-proliferative activities against cancer cells. HSA-fused hLF is a novel candidate for further application of hLF as biopharmaceuticals for intravenous administration., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background/purpose: Unresectable distal malignant biliary obstruction (DMBO) in patients with surgically altered anatomy is traditionally managed with percutaneous transhepatic biliary drainage (PTBD) and stenting because the anatomical features complicate the endoscopic approach to the biliary orifice. EUS-guided approaches recently emerged as alternative treatments; however, limited data comparing the procedures are available. The aim of this study was to compare EUS-antegrade biliary stenting (ABS) with PTBD for DMBO in patients with surgically altered anatomy., Methods: The medical records of patients who underwent EUS-ABS or PTBD for the management of DMBO and had a history of upper intestinal surgery at two tertiary centers between 2007 and 2019 were retrospectively evaluated. The study outcomes were technical, clinical, and internalization success rates and adverse event rates., Results: Of the 64 enrolled patients, 35 underwent EUS-ABS and 29 had PTBD. Basic characteristics including age, sex, performance status, primary malignancy, and reconstruction method did not differ significantly between groups. The technical, clinical, and internalization success rates in the EUS-ABS and PTBD groups were 97.1% vs 96.6% (P = 1.00), 97.1% vs 93.1% (P = .586), and 97.1% vs 75.9% (P = .01), respectively. The adverse event rate was 11.4% vs 27.6% (P = .119). No significant long-term difference was seen in time to recurrent biliary obstruction and survival. Multivariate analysis confirmed EUS-ABS was not an independent risk factor for survival., Conclusions: Similar to PTBD, EUS-ABS can effectively and safely manage DMBO in patients with surgically altered anatomy. Further well-designed trials are warranted to confirm these findings., (© 2020 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

We retrospectively investigated the use of oral hydromorphone for cancer pain. Nineteen patients treated for cancer pain with oral hydromorphone were reviewed in this study. Cancers had occurred in the gastrointestinal (n=4), lung(n=3), breast(n=2), bone and soft tissue(n=2), hematological(n=2), and others(n=6). The administered opioids before switching to hydromorphone were morphine, oxycodone, and tapentadol. The mean oral morphine equivalent daily dose (OMEDD)was 89.3 mg. The average dose of hydromorphone administered was 16.4 mg/day, and average NRS 10(numerical rating scale: 0-10)scores of cancer pain before and after switching were 4.1 and 3.8, respectively, showing no significant differences. In this study, switching from other opioids to oral hydromorphone was feasible with an approved conversion ratio, ie, an oral hydromorphone-to-oral morphine ratio of 1:5. No severe adverse effects were observed. The oral hydromorphone extended-release formulation was administered every 24 h, as a tiny tablet formulation that is preferable owing to easy administration and adherence.

In occupational settings, smokers may take quitting smoking seriously if they experienced long-term sick leave due to cancer or cardiovascular disease (CVD). However, no study has elucidated the smoking cessation rate after long-term sick leave. We examined the smoking cessation rate after long-term sick leave due to cancer and CVD in Japan. We followed 23 survivors who experienced long-term sick leave due to cancer and 39 survivors who experienced long-term sick leave due to CVD who reported smoking at the last health exam before the leave. Their smoking habits before and after the leave were self-reported. Logistic regression was used to calculate adjusted smoking cessation rates. Smoking cessation rate after long-term sick leave due to cancer was approximately 70% and that due to CVD exceeded 80%. The adjusted smoking cessation rate was 67.6% (95% confidence interval [CI]: 47.0, 88.2) for cancer and 80.7% (95% CI: 67.7, 93.8) for CVD. Smoking cessation rate after a longer duration of sick leave (≥60 d) tended to increase for both CVD and cancer. Although any definite conclusion cannot be drawn, the data suggest that smoking cessation rate after long-term sick leave due to CVD is slightly higher than that for cancer.

Background: Recently, a novel 22-gauge needle with three symmetric needle points and crown-shaped cutting heels, known as a Franseen needle, has been developed for endoscopic ultrasound-guided fine needle biopsy (EUS-FNB)., Aim: To assess the histological material acquisition rate and histological diagnostic capability of the 22-gauge Franseen needle (AC22) during EUS-FNB for solid lesions., Methods: This study was designed as an open-label, multicenter, prospective, single-arm pilot study of EUS-FNB using AC22 for the diagnosis of solid lesions. Three passes of FNB using AC22 were performed for all lesions. The primary endpoints were the histological material acquisition rate and histological diagnostic capability. The secondary endpoints were the technical success rate, quality of histological samples, number of passes for diagnosis, and safety., Results: Between September 2017 and May 2018, 75 patients were enrolled. The final diagnoses were malignancy in 65 and benign in 10. Three passes of FNB were technically successful in all patients. The sensitivity, specificity, and accuracy for the malignancy of histological analyses were 92.3% (60/65), 100% (10/10), and 93.3% (70/75), respectively, for the first pass and 95.4% (62/65), 100% (10/10), and 96% (72/75), respectively, for combined three passes. The diagnostic yield plateaued after the second pass. Sufficient tissue samples for histological interpretation were obtained in 96% (72/75) and 100% (75/75) patients for the single pass and combined three passes, respectively. Two patients (2.7%) developed mild pancreatitis as an adverse event., Conclusion: EUS-FNB using AC22 showed high histological diagnostic capability with the high first pass yield., Clinical Trials Registry: UMIN Clinical Trials Registry (UMIN ID: UMIN000036641).

The main effectors in tumor control are the class I MHC molecule-restricted CD8 + cytotoxic T lymphocytes (CTLs). Tumor-specific CTL induction can be regulated by dendritic cells (DCs) expressing both tumor-derived epitopes and co-stimulatory molecules. Immunosuppressive tolerogenic DCs, having down-regulated co-stimulatory molecules, are seen within the tumor mass and can suppress tumor-specific CTL induction. The tolerogenic DCs expressing down-regulated XCR1 + CD141 + appear to be induced by tumor-derived soluble factors or dexamethasone, while the immunogenic DCs usually express XCR1 + CD141 + molecules with a cross-presentation function in humans. Thus, if tolerogenic DCs can be reactivated into immunogenic DCs with sufficient co-stimulatory molecules, tumor-specific CD8 + CTLs can be primed and activated in vivo. In the present study, we converted human tolerogenic CD141 + DCs with enhanced co-stimulatory molecule expression of CD40, CD80, and CD86 through stimulation with non-toxic mycobacterial lipids such as mycolic acid (MA) and lipoarabinomannan (LAM), which synergistically enhanced both co-stimulatory molecule expression and interleukin (IL)-12 secretion by XCR1 + CD141 + DCs. Moreover, MA and LAM-stimulated DCs captured tumor antigens and presented tumor epitope(s) in association with class I MHCs and sufficient upregulated co-stimulatory molecules to prime naïve CD3 + T cells to become CD8 + tumor-specific CTLs. Repeat CD141 + DC stimulation with MA and LAM augmented the secretion of IL-12. These findings provide us a new method for altering the tumor environment by converting tolerogenic DCs to immunogenic DCs with MA and LAM from Mycobacterium tuberculosis.

This study develops and examines the validity and reliability of 2 scales, respectively, for evaluating nursing care and the experience of difficulties providing nursing care for dying patients with cancer and their families. A cross-sectional anonymous questionnaire was administered to nursing staff caring for dying patients with cancer and their families in 4 general hospitals and a university hospital in Japan. The instruments assessed were the Nursing Care Scale for Dying Patients and Their Families (NCD) and the Nurse's Difficulty Scale for Dying Patients and Their Families (NDD). Of the 497 questionnaires sent to nurses, 401 responses (80%) were analyzed. Factor analyses revealed that the NCD and NDD consisted of 12 items with 4 subscales: "symptom management," "reassessment of current treatment and nursing care," "explanation to family," and "respect for the patient and family's dignity before and after death." These scales had sufficient convergent and discriminative validity, sufficient internal consistency (α of subscales: NCD, 0.71-0.87; NDD, 0.74-0.93), and sufficient test-retest reliability (intraclass correlation coefficient of subscales: NCD, 0.59-0.81; NDD, 0.67-0.82) to be used as self-assessments and evaluation tools in education programs to improve the quality of nursing care for the dying patients and their families.

Purpose: This study aimed to identify support needs among young cancer patients regarding fertility-related issues to describe multidimensional support provided by nonphysician health care providers., Methods: Participants were cancer patients and their families who contacted the Hotline for Cancer Treatment and Reproduction at National Cancer Center Hospital in Japan. Medical charts were analyzed through content analysis., Results: A total of 51 participants met the inclusion criteria, of which 32 cases (63%) involved patients themselves, 13 (25%) patients' family members, and 6 (12%) both patients and their families. About patients' demographic status, 40% of the patients were female and 28% were in their thirties. Gynecological and breast cancer patients were the majority, and 24 patients (47%) had not yet started cancer treatment. As a result of content analysis regarding support needs, 9 categories and 55 codes were extracted. The categories included information about risk of infertility, information about means to maintain reproductive function, referral to specialists, support for economic burden, support for worry about cancer progression, support for psychological distress upon facing the risk of infertility, support for communication with oncologists, support for family relationships, and decisional aid., Conclusions: This study suggests that nonphysician health care providers should acquire knowledge about fertility preservation and provide psychological support within their specialties.

Objective:: There are no instruments evaluating the processes and outcomes of dying care right before and after death. Therefore, we developed and examined the validity and reliability of 2 scales for evaluating dying care processes and outcomes before and after death., Methods:: A cross-sectional, anonymous questionnaire was administered to bereaved family members of patients with cancer who had died in 5 facilities. We evaluated the Dying Care Process Scale for Bereaved Family Members (DPS-B) and the Dying Care Outcome Scale for Bereaved Family Members (DOS-B) with 345 bereaved family members., Results:: A factor analysis revealed that DPS-B and DOS-B each consisted of 4 subscales. For the DPS-B, they were "symptom management," "respect for the patient's dignity before and after death," "explanation to the family," and "family care." For the DOS-B, they were "peaceful dying process for the patient," "being respected as a person before and after death," "good relationship between the patient and family," and "peaceful dying process for the family." Both DPS-B and DOS-B had sufficient convergent and discriminative validity, sufficient internal consistency (DPS-B: α = 0.91 and subscales' αs = 0.78-0.91; DOS-B: α = 0.91 and subscales' αs = 0.78-0.94), and sufficient test-retest reliability (DPS-B: intraclass correlation coefficient [ICC] of total score = 0.79 and subscales = 0.55-0.79; DOS-B: ICC of total score = 0.88 and subscales = 0.70-0.88)., Significance of Results:: Both DPS-B and DOS-B are valid and reliable scales for evaluating the dying care processes and outcomes before and after death from the bereaved family members' perspectives.

Background: The effect of smoking on mortality in working-age adults remains unclear. Accordingly, we compared the effects of cigarette smoking and smoking cessation on total and cause-specific mortality in a Japanese working population. Methods and Results: This study included 79,114 Japanese workers aged 20-85 years who participated in the Japan Epidemiology Collaboration on Occupational Health Study. Deaths and causes of death were identified from death certificates, sick leave documents, family confirmation, and other sources. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated via Cox proportional hazards regression. During a maximum 6-year follow-up, there were 252 deaths in total. Multivariable-adjusted HRs (95% CIs) for total mortality, cardiovascular disease (CVD) mortality, and tobacco-related cancer mortality were 1.49 (1.10-2.01), 1.79 (0.99-3.24), and 1.80 (1.02-3.19), respectively, in current vs. never smokers. Among current smokers, the risks of total, tobacco-related cancer, and CVD mortality increased with increasing cigarette consumption (P trend <0.05 for all). Compared with never smokers, former smokers who quit <5 and ≥5 years before baseline had HRs (95% CIs) for total mortality of 1.80 (1.00-3.25) and 1.02 (0.57-1.82), respectively., Conclusions: In this cohort of workers, cigarette smoking was associated with increased risk of death from all and specific causes (including CVD and tobacco-related cancer), although these risks diminished 5 years after smoking cessation.

Objectives: Although transthyretin (TTR) is a nutritional indicator and is influenced by systemic inflammation, it may be a good prognostic indicator for cancer patients in palliative care settings. This study investigates the correlation between low TTR levels and survival among cancer patients in palliative care settings., Methods: This was a sub-analysis of a prospective, multicenter cohort study. Patients who had advanced-stage cancer and who were newly referred to palliative care services were eligible to participate; however, those receiving anti-tumor therapy were excluded. Survival analyses were performed to clarify predictors of poor prognosis., Results: A total of 144 patients were enrolled (45.1% female; median age, 72 years). Cox regression analysis revealed that low TTR levels (<10.9 mg/l) (hazard ratio 1.74, P = 0.025), poor muscle power (1.71, P = 0.045), and fatigue (1.89, P = 0.024) were predictors of poor prognosis. Median survival in patients with low TTR levels (<10.9 mg/l) was 26 days, which was significantly shorter than those with high TTR levels (≥10.9 mg/l) (50 days; P < 0.001)., Conclusion: Low TTR levels may be indicators for poor prognosis among cancer patients in palliative care settings.

Purpose: The American Society of Clinical Oncology (ASCO) Clinical Practice guidelines recommend that physicians, nurses, social workers, and other health care providers should be prepared to discuss the risk of infertility with patients. We conducted an educational program for non-physician health care providers regarding fertility preservation and evaluated the effects of the educational program., Methods: The 4-h educational program consisted of lectures about infertility as a potential risk of cancer treatment, fertility preservation, and psychosocial support. Knowledge, confidence, institutional change, and self-practice were assessed pre-program, immediately post-program, and 6 months post-program., Results: Of 124 participants who joined the program, 74 completed and returned the follow-up survey 6 months after the program. Sixty-one percent of the participants were nurses, 27% were social workers, and 4% were psychologists. The scores for confidence and knowledge increased between pre- and immediate post-program periods (p < 0.01), and between pre- and 6-month post-program periods (p < 0.01). The knowledge score was 52, 76, and 71% at the 3 points respectively. The participants became more likely to disseminate fertility preservation counseling at their institutions (p < 0.01) and use informational resources (p < 0.01). Overall, self-practice and institutional support did not change., Conclusions: The study revealed that this educational program is applicable for non-physicians to learn about fertility preservation. The participants improved significantly in confidence and knowledge, but not in counseling skills.

A number of epidemiological, clinical, and experimental researches have indicated that administration of green tea appears to have anti-cancer activity. According to findings of laboratory cell culture studies, a diverse mechanism has been observed underlying the effects of green tea catechins against cancer. These mechanisms include anti-oxidant activity, cell cycle regulation, receptor tyrosine kinase pathway inhibition, immune system modulation, and epigenetic modification control. This review discusses the results of these studies to provide more insight into the effects of green tea administration on cancers observed to date in this research field.

The tumor microenvironment (TME) contains stromal cells in a complex interaction with cancer cells. This relationship has become better understood with the use of fluorescent proteins for in vivo imaging, originally developed by our laboratories. Spectrally-distinct fluorescent proteins can used for color-coded imaging of the complex interaction of the tumor microenvironment in the living state using cancer cells expressing a fluorescent protein of one color and host mice expressing another-color fluorescent protein. Cancer cells engineered in vitro to express a fluorescent protein were orthotopically implanted into transgenic mice expressing a fluorescent protein of a different color. Confocal microscopy was then used for color-coded imaging of the TME. Color-coded imaging of the TME has enabled us to discover that stromal cells are necessary for metastasis. Patient-derived orthotopic xenograft (PDOX) tumors were labeled by first passaging them orthotopically through transgenic nude mice expressing either green, red, or cyan fluorescent protein in order to label the stromal cells of the tumor. The colored stromal cells become stably associated with the PDOX tumors through multiple passages in transgenic colored mice or non-colored mice. The fluorescent protein-expressing stromal cells included cancer-associated fibroblasts and tumor-associated macrophages. The cancer cells in PDOX models can also be labeled with a telomerase-dependent adenovirus containing the gene for green fluorescent protein. Using this model, specific cancer-cell or stromal-cell targeting by potential therapeutics can be visualized. Color-coded imaging enabled the visualization of apparent fusion of cancer and stromal cells. Color-coded imaging is a powerful tool visualizing the interaction of cancer and stromal cells during cancer progression and treatment., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Long-term sick-leave is a major public health problem, but data on its incidence in Japan are scarce. We aimed to present reference data for long-term sick-leave among private sector employees in Japan., Methods: The study population comprised employees of 12 companies that participated in the Japan Epidemiology Collaboration on Occupational Health Study. Details on medically certified sick-leave lasting ≥30 days were collected from each company. Age- and sex-specific incidence rate of sick-leave was calculated for the period of April 2012 to March 2014., Results: A total of 1422 spells in men and 289 in women occurred during 162,989 and 30,645 person-years of observation, respectively. The three leading causes of sick-leave (percentage of total spells) were mental disorders (52%), neoplasms (12%), and injury (8%) for men; and mental disorders (35%), neoplasms (20%), and pregnancy-related disease (14%) for women. Incidence rate of sick-leave due to mental disorders was relatively high among men in their 20s-40s but tended to decrease with age among women. Incidence rate of sick-leave due to neoplasms started to increase after age 50 in men and after age 40 in women, making neoplasms the leading cause of sick-leave after age 50 for women and after age 60 for men and the second leading cause after age 40 for women and after age 50 for men. Pregnancy-related disease was the second leading cause of sick-leave among women aged 20-39 years., Conclusions: These results suggest that mental disorder, neoplasms, and pregnancy-related disease are the major causes of long-term sick-leave among private sector employees in Japan., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: To monitor quality of life (QOL) for patients with cancer in a large population-based survey, we developed a short QOL and quality-of-care (QOC) questionnaire. To determine the validity and reliability of this new questionnaire for evaluating QOL in patients with cancer., Methods: Outpatients and inpatients at National Cancer Center Hospital East were administered a questionnaire, including the following items-the short QOL and QOC questionnaire (physical distress, pain, emotional distress, walk burden, and need for help with self-care; perceived general health status; and satisfaction with medical care and treatment by doctor, communication with doctor, support by health-care staff other than doctor, care for physical symptoms such as pain, and psychological care), the Functional Assessment of Cancer Therapy-General (FACT-G), the Cancer Care Evaluation Scale (CCES) for patients, and demographic and medical data. We then readministered the short QOL and QOC questionnaire., Results: In total, 329 outpatients and 239 inpatients completed the survey (response rates: 80% and 90%, respectively). Total Cronbach α for the short QOL and QOC questionnaire was 0.83 for outpatients and 0.82 for inpatients. Items of the questionnaire correlated with cancer-specific measurements, FACT-G, and CCES. Intraclass correlation coefficients for all items of the questionnaire were 0.79 and 0.89 in each setting. Items of QOL and QOC did not correlate with each other., Conclusion: The validity and reliability of the short QOL and QOC questionnaire appear sufficient. This questionnaire enables continuous monitoring of patient QOL in large population-based surveys.

Objective: This study was designed to investigate pharmacological interaction between magnesium laxative and antacid in patients receiving opioid analgesic., Methods: Data obtained from a total of 441 eligible patients receiving opioid analgesic for the first time were retrospectively analysed. The incidence of constipation, defined as stool-free interval of 3 days and more within the first week of opioid intake, was compared between patients who took laxative alone and those who received laxative in combination with antacid., Key Findings: Laxatives were prescribed in 74% of patients, among them 61% received antacids such as proton pump inhibitor and H2 receptor blocker. Magnesia was the most commonly used laxative (89%). Constipation occurred in 21% and 55% of patients with and without laxatives, respectively. Antacids reversed the laxative action of lower doses (<2000 mg/day) but not higher doses (>2000 mg/day) of magnesia without affecting the effects of other laxatives. Therefore, it is suggested that both acid-dependent and acid-independent mechanisms may operate in the laxative action of magnesia, in which the former may be involved in the action of lower doses of magnesia., Conclusion: Care should be taken to avoid the unfavourable pharmacological interaction between low doses of magnesia and antacid., (© 2016 The Authors. Journal of Pharmacy and Pharmacology published by John Wiley & Sons Ltd on behalf of Royal Pharmaceutical Society.)

Context: Accurate prognoses are needed for patients with advanced cancer., Objectives: To evaluate the accuracy of physicians' clinical predictions of survival (CPS) and assess the relationship between CPS and actual survival (AS) in patients with advanced cancer in palliative care units, hospital palliative care teams, and home palliative care services, as well as those receiving chemotherapy., Methods: This was a multicenter prospective cohort study conducted in 58 palliative care service centers in Japan. The palliative care physicians evaluated patients on the first day of admission and followed up all patients to their death or six months after enrollment. We evaluated the accuracy of CPS and assessed the relationship between CPS and AS in the four groups., Results: We obtained a total of 2036 patients: 470, 764, 404, and 398 in hospital palliative care teams, palliative care units, home palliative care services, and chemotherapy, respectively. The proportion of accurate CPS (0.67-1.33 times AS) was 35% (95% CI 33-37%) in the total sample and ranged from 32% to 39% in each setting. While the proportion of patients living longer than CPS (pessimistic CPS) was 20% (95% CI 18-22%) in the total sample, ranging from 15% to 23% in each setting, the proportion of patients living shorter than CPS (optimistic CPS) was 45% (95% CI 43-47%) in the total sample, ranging from 43% to 49% in each setting., Conclusion: Physicians tend to overestimate when predicting survival in all palliative care patients, including those receiving chemotherapy., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Predicting the short-term survival in cancer patients is an important issue for patients, family, and oncologists. Although the prognostic accuracy of the surprise question has value in 1-year mortality for cancer patients, the prognostic value for short-term survival has not been formally assessed. The primary aim of the present study was to assess the prognostic value of the surprise question for 7-day and 30-day survival in patients with advanced cancer., Patients and Methods: The present multicenter prospective cohort study was conducted in Japan from September 2012 through April 2014, involving 16 palliative care units, 19 hospital-based palliative care teams, and 23 home-based palliative care services., Results: We recruited 2,425 patients and included 2,361 for analysis: 912 from hospital-based palliative care teams, 895 from hospital palliative care units, and 554 from home-based palliative care services. The sensitivity, specificity, positive predictive value, and negative predictive value of the 7-day survival surprise question were 84.7% (95% confidence interval [CI], 80.7%-88.0%), 68.0% (95% CI, 67.3%-68.5%), 30.3% (95% CI, 28.9%-31.5%), and 96.4% (95% CI, 95.5%-97.2%), respectively. The sensitivity, specificity, positive predictive value, and negative predictive value for the 30-day surprise question were 95.6% (95% CI, 94.4%-96.6%), 37.0% (95% CI, 35.9%-37.9%), 57.6% (95% CI, 56.8%-58.2%), and 90.4% (95% CI, 87.7%-92.6%), respectively., Conclusion: Surprise questions are useful for screening patients for short survival. However, the high false-positive rates do not allow clinicians to provide definitive prognosis prediction., Implications for Practice: The findings of this study indicate that clinicians can screen patients for 7- or 30-day survival using surprise questions with 90% or more sensitivity. Clinicians cannot provide accurate prognosis estimation, and all patients will not always die within the defined periods. The screened patients can be regarded as the subjects to be prepared for approaching death, and proactive discussion would be useful for such patients., (©AlphaMed Press.)

Introduction: Communicating with patients is clearly an integral part of physicians' practice, and introducing home hospice care is sometimes a difficult task for oncologists. The primary aims of this study were to clarify family-reported degree of emotional distress and the necessity for improvement in communication when introducing home hospice care, and to identify factors contributing to distress levels., Methods: A multicenter questionnaire survey was conducted involving 1,052 family members of cancer patients who died at home at 15 home-based hospice services throughout Japan., Results: A total of 616 responses were analyzed(effective response rate of 60%). Fifty-nine percent of the bereaved family members reported that they were distressed or very distressed in receiving information about home hospice care, and 30% reported considerable or much improvement was necessary. There were 6 determinants of family-reported degree of emotional distress and the necessity for improvement: 1 ) Family distress was experienced when the physician stated that the disease progression defeated medicine and nothing could be done for the patient. 2 ) The physicians' explanation did not match with the state of family preparation. 3 ) There was no intimacy between hospital physician and home physician. 4 ) Physicians did not make the atmosphere relaxing enough to allow families to ask questions. 5 ) Nurses did not follow up to generate additional ideas to supplement the physician's statement. 6 ) Family members experienced pressure to make a rash decision., Conclusion: In receiving information about transition of home care, a considerable number of families experienced high levels of emotional distress and felt a need for improvement in the communication style. This study proposes 6 strategies to alleviate family distress.

Purpose: This study aims to clarify the length of home hospice care, family-perceived timing of referrals, and their effects on the family-perceived quality of care and quality of death and dying of terminally ill cancer patients who died at home and identify the determinants of perceived late referrals., Methods: A multicenter questionnaire survey was conducted involving 1,052 family members of cancer patients who died at home supported by 15 home-based hospice services throughout Japan., Results: A total of 693 responses were analyzed (effective response rate, 66 %). Patients received home-based hospice care for a median of 35.0 days, and 8.0 % received home hospice care for less than 1 week. While 1.5 % of the families reported the timing of referrals as early, 42 % reported the timing as late or too late. The families of patients with a length of care of less than 4 weeks were more likely to regard the timing of referrals as late or too late. The patients of family members who regarded the timing of referrals as late or too late had a significantly lower perceived quality of care (effect size, 0.18; P = 0.039) and lower quality of death and dying (effect size, 0.15, P = 0.063). Independent determinants of higher likelihoods of perceived late referrals included: frequent visits to emergency departments, patient being unprepared for worsening condition, and patient having concerns about relationship with new doctor. Discharge nurse availability was independently associated with lower likelihoods of perceived late referrals., Conclusions: A significant number of bereaved families regarded the timing of referrals to home hospices as late, and the perceived timing was associated with the family-perceived quality of care and quality of death and dying. Systematic strategies to overcome the barriers related to perceived late referrals are necessary.

Purpose: We compared two health-related quality of life (HRQOL) instruments used for cancer patients [the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy-General (FACT-G)] to identify which instrument cancer patients most preferred., Methods: Adult cancer patients who had received cancer treatments within the previous 2 years (n = 395) completed both surveys; participants assessed the importance, necessity, and appropriateness of each as an indicator of their quality of life., Results: The patients significantly preferred the FACT-G over the EORTC QLQ-C30 as a more important (effect size (ES) = 0.37, P < 0.001), necessary (ES = 0.18, P < 0.001), and appropriate questionnaire (ES = 0.14, P = 0.005). The subgroups of patients with good performance status, and those who reported low levels of work disruption, significantly preferred the FACT-G more than the other. The corresponding correlation coefficients were the following: physical functioning and well-being subscale, r = 0.65; emotional functioning and well-being subscale, r = 0.60; social functioning and social/family well-being subscale, r = 0.00; and role functioning and functional well-being subscale, r = 0.41., Conclusions: We recommend using the FACT-G if the performance status of the subject is good, e.g., in outpatient or cancer survivor surveys, based on the observed patient preferences. When performance status is not good, an instrument should be chosen after considering the differences between their scale structures and social domains and based on the availability of disease-specific modules.

Background: Patients with advanced malignancies in non-complete remission (CR) have a dismal prognosis after HLA-matched hematopoietic stem cell transplantation (HSCT). T-cell-replete HLA-haploidentical HSCT has remarkable anti-leukemia/tumor effects on these patients, but also a high risk of severe/extensive graft-versus-host disease (GHVD). Post-transplantation cyclophosphamide (PTCY) is regarded as a GVHD-specific immunosuppressant in adults, but its feasibility is unknown in children., Methods: We performed a prospective feasibility study of PTCY at 50 mg/kg on day 3 for children with advanced leukemias or malignant solid tumors: refractory to chemotherapy or relapsed after conventional allogeneic HSCT. Conditioning consisted of fludarabine (180 mg/m2) and melphalan (140-210 mg/m2)., Results: Long-term engraftments were achieved in 11 patients (73.3%) after bone marrow transplantation (BMT, n = 13) or peripheral blood (PB) stem cell transplantation (n = 2). The incidence of severe acute GHVD was 25.0% and that of extensive chronic GVHD 0.0% after evaluable BMT. CR was achieved in 6/15 and partial response in 4/15 as the best response. Finally, 11/15 experienced disease progression/relapse, 2/15 suffered treatment-related mortality without evidence of disease, and 2/15 are alive in continuous CR., Conclusions: PTCY is feasible in children; however, for a better outcome in such patients with advanced malignancies, some modifications are anticipated.

Recent data have linked hypoxia, a classic feature of the tumor microenvironment, to the function of specific microRNAs (miRNAs); however, whether hypoxia affects other types of noncoding transcripts is currently unknown. Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs). Interestingly, several hypoxia-upregulated T-UCRs, henceforth named 'hypoxia-induced noncoding ultraconserved transcripts' (HINCUTs), are also overexpressed in clinical samples from colon cancer patients. We show that these T-UCRs are predominantly nuclear and that the hypoxia-inducible factor (HIF) is at least partly responsible for the induction of several members of this group. One specific HINCUT, uc.475 (or HINCUT-1) is part of a retained intron of the host protein-coding gene, O-linked N-acetylglucosamine transferase, which is overexpressed in epithelial cancer types. Consistent with the hypothesis that T-UCRs have important function in tumor formation, HINCUT-1 supports cell proliferation specifically under hypoxic conditions and may be critical for optimal O-GlcNAcylation of proteins when oxygen tension is limiting. Our data gives a first glimpse of a novel functional hypoxic network comprising protein-coding transcripts and noncoding RNAs (ncRNAs) from the T-UCRs category.

Many epidemiological studies and a large number of experimental studies using a variety of animal models have observed that consumption or administration of green tea appears to exert cancer chemopreventive activity. Based on the results of numerous laboratory cell culture investigations, several mechanisms have been hypothesized to underlie the anti-cancer activity of green tea catechins, especially that of (-)-epigallocatechin-3-gallate (EGCG), the most abundant and active constituent in green tea. These mechanisms include promotion of anti-oxidant activity, inhibition of NF-κB and AP-1, regulation of the cell cycle, inhibition of receptor tyrosine kinase pathways, control of epigenetic modifications, and modulation of the immune system. Several recent interventional studies examining the anti-carcinogenic properties of green tea catechins in humans have yielded promising results that suggest the possibility of their application to human clinical trials. This review article analyzes the results of these studies to explicate the effects of consumption or administration of green tea and its constituents on malignancies observed to date and discuss future directions in this research field.

Purpose: Drinking green tea daily is part of Japanese culture, and various studies have revealed that green tea is a cancer preventive. We here review our progress in cancer prevention with green tea on 12 main topics, from basic to clinical level. TOPICS AND METHODS: Biochemical and biological studies of green tea catechins, a prospective cohort study, preclinical safety trials with tablets of green tea extract, double-blind randomized clinical phase II prevention trial for recurrence of colorectal adenomas, and synergistically enhanced inhibition by the combination of green tea catechins and anticancer drugs. All results were significant, including human studies with informed consent., Results: Drinking 10 Japanese-size cups of green tea per day delayed the cancer onset of humans 7 years for females. For tertiary cancer prevention, consuming 10 cups of green tea per day fortified by green tea tablets, 50 %, significantly prevented the recurrence of colorectal adenomas. A minimum effective amount of green tea catechins for cancer prevention was found in humans. In addition, the combination of green tea catechins and anticancer drugs engendered a new cancer therapeutic strategy., Conclusion: The consumption of 10 Japanese-size cups of green tea per day is a significant factor in primary cancer prevention for the general population, and the preventive effect on recurrence of colorectal adenomas in patients is vital evidence in tertiary cancer prevention.

Recent studies indicate that receptor tyrosine kinases (RTKs), which play important roles in cell proliferation, are one of the possible targets of green tea catechins (GTCs) in cancer cell growth inhibition. (-)-Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, inhibits cell proliferation and induces apoptosis in various types of cancer cells, including colorectal cancer and hepatocellular carcinoma cells, by blocking the activation of the epidermal growth factor receptor (EGFR) family of RTKs. EGCG inhibits the activation of insulin-like growth factor-1 receptor (IGF-1R) and VEGFR2, the other members of the RTK family, and this effect is also associated with the anticancer and chemopreventive properties of this agent. EGCG suppresses the activation of EGFR in part by altering membrane lipid organization and causing the subsequent inhibition of the dimerization and activation of this receptor. Preliminary trials have shown that GTCs successfully prevent the development and progression of precancerous lesions, such as colorectal adenomas, without causing severe adverse effects. The present report reviews evidence indicating that GTCs exert anticancer and chemopreventive effects by inhibiting the activation of specific RTKs, especially EGFR, IGF-1R, and VEGFR2, and concludes that targeting RTKs and their related signaling pathways by using tea catechins could be a promising strategy for the prevention of human cancers., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

MicroRNAs (miRNAs) are short 19- to 24-nt RNA molecules that have been shown to regulate the expression of other genes in a variety of eukaryotic systems. Abnormal expression of miRNAs has been observed in several human cancers, and furthermore, germ-line and somatic mutations in human miRNAs were recently identified in patients with chronic lymphocytic leukemia. Thus, human miRNAs can act as tumor suppressor genes or oncogenes, where mutations, deletions, or amplifications can underlie the development of certain types of leukemia. In addition, previous studies have shown that miRNA expression profiles can distinguish among human solid tumors from different organs. Because a single miRNA can simultaneously influence the expression of two or more protein-coding genes, we hypothesized that miRNAs could be candidate genes for cancer risk. Research in complex trait genetics has demonstrated that genetic background determines cancer susceptibility or resistance in various tissues, such as colon and lung, of different inbred mouse strains. We compared the genome positions of mouse tumor susceptibility loci with those of mouse miRNAs. Here, we report a statistically significant association between the chromosomal location of miRNAs and those of mouse cancer susceptibility loci that influence the development of solid tumors. Furthermore, we identified distinct patterns of flanking DNA sequences for several miRNAs located at or near susceptibility loci in inbred strains with different tumor susceptibilities. These data provide a catalog of miRNA genes in inbred strains that could represent genes involved in the development and penetrance of solid tumors.

Background: The finding of hemizygous or homozygous deletions at band 14 on chromosome 13 in a variety of neoplasms suggests the presence of a tumor-suppressor locus telomeric to the RB1 gene., Methods: We studied samples from 216 patients with various types of sporadic tumors or idiopathic pancytopenia, peripheral-blood samples from 109 patients with familial cancer or multiple cancers, and control blood samples from 475 healthy people or patients with diseases other than cancer. We performed functional studies of cell lines lacking ARLTS1 expression with the use of both the full-length ARLTS1 gene and a truncated variant., Results: We found a gene at 13q14, ARLTS1, a member of the ADP-ribosylation factor family, with properties of a tumor-suppressor gene. We analyzed 800 DNA samples from tumors and blood cells from patients with sporadic or familial cancer and controls and found that the frequency of a nonsense polymorphism, G446A (Trp149Stop), was similar in controls and patients with sporadic tumors but was significantly more common among patients with familial cancer than among those in the other two groups (P=0.02; odds ratio, 5.7; 95 percent confidence interval, 1.3 to 24.8). ARLTS1 was down-regulated by promoter methylation in 25 percent of the primary tumors we analyzed. Transfection of wild-type ARLTS1 into A549 lung-cancer cells suppressed tumor formation in immunodeficient mice and induced apoptosis, whereas transfection of truncated ARLTS1 had a limited effect on apoptosis and tumor suppression. Microarray analysis revealed that the wild-type and Trp149Stop-transfected clones had different expression profiles., Conclusions: A genetic variant of ARLTS1 predisposes patients to familial cancer., (Copyright 2005 Massachusetts Medical Society.)

A large number of tiny noncoding RNAs have been cloned and named microRNAs (miRs). Recently, we have reported that miR-15a and miR-16a, located at 13q14, are frequently deleted and/or down-regulated in patients with B cell chronic lymphocytic leukemia, a disorder characterized by increased survival. To further investigate the possible involvement of miRs in human cancers on a genome-wide basis, we have mapped 186 miRs and compared their location to the location of previous reported nonrandom genetic alterations. Here, we show that miR genes are frequently located at fragile sites, as well as in minimal regions of loss of heterozygosity, minimal regions of amplification (minimal amplicons), or common breakpoint regions. Overall, 98 of 186 (52.5%) of miR genes are in cancer-associated genomic regions or in fragile sites. Moreover, by Northern blotting, we have shown that several miRs located in deleted regions have low levels of expression in cancer samples. These data provide a catalog of miR genes that may have roles in cancer and argue that the full complement of miRs in a genome may be extensively involved in cancers.

Bacterial superantigens (SAGs) bind to cognate Vbeta elements of T-cell receptors on T-cells and to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells to activate T-cell subsets expressing the Vbeta elements. We examined the possibility that the direct binding of SAGs (staphylococcal enterotoxins B [SEB] and A [SEA]) to tumor cells decreases the toxicity of SAGs, and that antitumor immunity can be induced with the aid of T-helper-1 (Th1)-type cytokines and monokines released from T-cells and monocytes, respectively, by activation with SAGs. In this context, we have developed a general method for conjugating SEB and SEA directly to tumor cells with a heterobifunctional cross linking agent, N-(gamma- maleimidobutyryloxy) sulfosuccinimide sodium salt. Using this method, we have succeeded in conjugating SEB to a sufficient extent as to induce strong tumor immunity. Both in vitro T-cell culture with SEB-bearing Meth A cells and in vivo immunization with SEB-bearing Meth A cells induce strong antitumor activity. These results suggest that the direct conjugation of SAGs including SEB and SEA to tumor cells is a powerful and useful method for immunotherapy of cancer.

Electroporation is a method for introducing DNA into cells by using a high-voltage electric field. This method is very simple and easily manipulated. We describe here a method for the modification of tumor cells with the Fas/Apo-1 (CD95) antigen-gene and Fas ligand (FasL)-gene transfection through the use of electroporation, and suggest that the Fas-FasL system is a good target for the induction of apoptosis-mediated antitumor activity. The Fas receptor/ligand system induces apoptosis and plays an important role in regulation of the immune system. In the method described, hepatoma MH134 (Fas- and FasL-) is transfected with murine Fas and FasL cDNA. A single administration of monoclonal anti-Fas antibody efficiently suppresses the growth of F6b (MH134+Neo+Fas) tumors but not that of N1d (MH134+Neo) tumors in gld/gld lpr/lpr mice. MH134+Neo+FasL tumor cells were rejected after the induction of inflammation with infiltration of neutrophils in mice. These results suggest that electroporation and Fas-mediated apoptosis are a good method for inducing of antitumor activity.

Objective: To detect the location and geographical features of gene mutation of the cancer based on 30,709 clinical tumor biopsies., Methods: Thirty thousand seven hundred and nine cases of tumor biopsy materials were collected from the Department of Pathology of Nantong Cancer Hospital between June 1974 and December 1987. The address of the village and county of patients was collected and statistical analysis was performed on data from lab examination. DNA sequencing of 31 cases of hepatocellular carcinoma (HCC) was performed at the Department of Pathology of the Medical College of Tokyo University, Japan., Results: The data suggested that different carcinomas occurred predominantly in some districts and the frequency and type of mutation of the P53 gene in the HCC were different in different districts., Conclusion: It seems that based on the clinical biopsy materials, carcinomas of the uterus cervix (CC) and nasopharynx tend to occur in some districts of Nantong City and the frequency and type of mutation of the gene P53 of the HCC were different in different districts. The reason for this is not understood and further study will be done.

5-(3-Aminopropyl)amino-7,10-dihydroxy-2-(2-hydroxethyl)-aminoethyl -6H-pyrazolo[4,5,1-de]acridin-6-one dihydroxy-chloride (KW-2170), a novel derivative of pyrazoloacridone, was selected and evaluated for its antitumor activity and toxicity in mice. KW-2170 exhibited antitumor activity superior to adriamycin (ADM) against Sarcoma 180, breast carcinoma MM102 and fibrosarcoma Meth A inoculated s.c. in mice. Its therapeutic index (LD10/ED50) was higher than that of ADM on two murine carcinoma models, MM102 and Meth A. KW-2170 showed significant antitumor activity against 17 human tumor xenografts of a total of 24 tumors tested and the total tumor response rate by treatment with KW-2170 was significantly higher than that by ADM (70.8 versus 58.3%). In particular, human lung carcinoma was highly sensitive to KW-2170, and a marked tumor regression was observed on Lu-65 and Lu-99 human lung carcinoma xenograft models. Ovary and pancreas carcinomas were also sensitive to the drug. Additionally, its therapeutic index was also high on these human carcinoma models in comparison with that of ADM. The best antitumor efficacy of KW-2170 was observed by a weekly treatment schedule followed by a single treatment schedule and a successive administration schedule also tended to be toxic to the hosts. KW-2170 exhibited very low cross-resistance against four lines of multidrug resistant tumors expressing high levels of P-glycoprotein, and the drug showed significant antitumor activity against ADM-resistant human ovary carcinoma A2780/ADM and against nasopharynx carcinoma KB-A1 xenografts which were not sensitive to ADM. These results indicate that KW-2170 has a very potent antitumor activity and is feasible as a new antitumor drug against ADM-refractory solid tumors in clinics.

Previous primate and rodent studies suggested that interleukin-1 alpha (IL-1 alpha) caused changes in the secretion of pituitary, adrenal, thyroid, and gonadal hormones, as well as acute-phase reactants. Plasma samples were obtained after IL-1 alpha and beta treatment in cancer patients to document the changes in endocrine function suggested by the animal models. Successive groups of patients were treated at IL-1 alpha doses of 0.01, 0.03, 0.1, 0.3, and 1.0 microgram/kg, given daily as a 15-min intravenous bolus. IL-1 beta was given at 0.1 microgram/kg by the same route and time course. After the first dose of IL-1, statistically significant elevations of a.m. and p.m. cortisol, growth hormone (GH), and prolactin (PRL) occurred. Thyroid-stimulating hormone (TSH) and C-reactive protein (CRP) were elevated by the sixth treatment day. Testosterone decreased significantly in male patients. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were more variable but decreased in most patients. The changes in cortisol, GH, PRL, TSH, CRP, FSH, LH, and testosterone resolved after treatment and did not result in clinically apparent endocrinopathies. Bolus doses of IL-1 alpha and beta cause significant changes in many endocrine laboratory parameters and influence the in vivo activities of multiple homeostatic endocrine functions in human beings.

The characteristics of low mobility cells (LMC) in the peripheral blood mononuclear cells (PBMC) of cancer patients were studied using a Parmoquant-L, a fully automated electrophoresis instrument, and a fluorescence-activated cell sorter (FACS). The L/H ratio (%) of LMC (less than 0.95 micron/s/V/cm) to high mobility cells (HMC) (greater than or equal to 0.95) was used to analyze the electrophoretic mobility (EPM) histogram of PBMC. In the cancer patient, the L/H ratio increased as a result of the appearance of LMC. As the ratio closely correlated with clinical stage of cancer, recurrence of cancer, and performance status in the patients, the method is a useful parameter for prognosis of cancer, practically, for early detection of recurrence in the follow-up study of cancer patients. The EPM of monocytes and subsets of lymphocytes was determined to characterize LMC. Monocytes were in LMC. T-Cells such as helper/inducer (Leu-3+), suppressor (Leu-2+Leu-15+) and cytotoxic (Leu-2+Leu-15-) cells and natural killer (NK) cells (Leu-7+ or Leu-11+) were in HMC. The percentage of monocytes correlated significantly with the mean EPM of PBMC. In cancer patients, the percentage of monocytes increased significantly. On the other hand, suppressor T-cells did not increase enough to account for LMC. The appearance of suppressor T-cells correlated with that of monocytes. These results suggest that LMC in cancer patients consisted of mainly monocytes rather than suppressor T-cells.