Genetic and epigenetic alterations in precursor lesions of endometrial endometrioid carcinoma.

The hyperplasia-carcinoma sequence is a stepwise tumourigenic programme towards endometrial cancer in which normal endometrial epithelium becomes neoplastic through non-atypical endometrial hyperplasia (NAEH) and atypical endometrial hyperplasia (AEH), under the influence of unopposed oestrogen. NAEH and AEH are known to exhibit polyclonal and monoclonal cell growth, respectively; yet, aside from focal PTEN protein loss, the genetic and epigenetic alterations that occur during the cellular transition remain largely unknown. We sought to explore the potential molecular mechanisms that promote the NAEH-AEH transition and identify molecular markers that could help to differentiate between these two states. We conducted target-panel sequencing on the coding exons of 596 genes, including 96 endometrial cancer driver genes, and DNA methylome microarrays for 48 NAEH and 44 AEH lesions that were separately collected via macro- or micro-dissection from the endometrial tissues of 30 cases. Sequencing analyses revealed acquisition of the PTEN mutation and the clonal expansion of tumour cells in AEH samples. Further, across the transition, alterations to the DNA methylome were characterised by hypermethylation of promoter/enhancer regions and CpG islands, as well as hypo- and hyper-methylation of DNA-binding regions for transcription factors relevant to endometrial cell differentiation and/or tumourigenesis, including FOXA2, SOX17, and HAND2. The identified DNA methylation signature distinguishing NAEH and AEH lesions was reproducible in a validation cohort with modest discriminative capability. These findings not only support the concept that the transition from NAEH to AEH is an essential step within neoplastic cell transformation of endometrial epithelium but also provide deep insight into the molecular mechanism of the tumourigenic programme. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Coexistence of ovarian cancer and peritoneal tuberculosis: a case report.

Peritoneal tuberculosis (TB) is known to mimic advanced ovarian cancer. In this case report, we describe a unique case of ovarian cancer (endometrioid carcinoma grade 3) at the International Federation of Gynecology and Obstetrics (FIGO) stage IC1 with pulmonary and peritoneal TB, which was suspected preoperatively to be a coexistence of advanced ovarian cancer and pulmonary TB. A 68-year-old woman presented with a prominent abdominal mass and fever. Laboratory investigations, imaging, and sputum analysis indicated a probable diagnosis of ovarian cancer at FIGO stage IIIC, characterized by peritoneal dissemination and para-aortic lymph node metastasis, which was further complicated by coexisting pulmonary TB. Surgical management included total abdominal hysterectomy, bilateral salpingo-oophorectomy, and partial omentectomy. Intraoperatively, the tumor was localized to the right ovary with significant peritoneal thickening and adhesions indicative of peritoneal TB. The surgery was completed without apparent complications. Postoperative histopathological evaluation confirmed grade 3 endometrioid carcinoma in the right ovary along with evidence of peritoneal TB. Given the extent of adhesions attributed to TB, lymph node dissection for staging was deemed challenging and was thus not pursued. Initiation of anti-TB treatment on postoperative day 2 resulted in marked regression of the preoperatively identified pulmonary nodules and para-aortic lymph node enlargement, suggesting their inflammatory origin from TB. Although postoperative chemotherapy is typically advocated for patients with stage IC1 endometrioid carcinoma grade 3, the patient opted against it. Consequently, no adjuvant therapy was administered and the patient remained under close observation.

Ovarian surveillance including endometrial cytology for patients with hereditary breast and ovarian cancer before risk-reducing salpingo-oophorectomy: A retrospective analysis.

AIM: Ovarian surveillance in women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy has been controversial. Therefore, this study aimed to demonstrate the clinical features of ovarian surveillance at our institution using a technique that combines serum cancer antigen 125 measurements, transvaginal ultrasonography, and uterine endometrial cytology. METHODS: We retrospectively examined 65 women, who had not undergone risk-reducing salpingo-oophorectomy diagnosed with hereditary breast and ovarian cancer between 2000 and 2021 at our hospital. Clinical information was obtained and analyzed through a chart review. The details of the treatment course were reviewed for patients who had developed ovarian cancer. RESULTS: Overall, 5 of the 65 women were diagnosed with ovarian cancer based on abnormal findings during periodic surveillance. All patients who developed ovarian cancer were asymptomatic, even if the cancer was at an advanced stage. Two of the 65 patients had endometrial cytology abnormalities, both of whom had ovarian cancer. All patients who developed ovarian cancer underwent primary debulking surgery, and complete gross resection was achieved. None of the patients experienced ovarian cancer recurrence. CONCLUSIONS: The ovarian surveillance strategy at our institution for women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy can identify asymptomatic ovarian cancer and contribute to achieving complete gross resection during primary surgery. Ovarian surveillance may contribute to a reduction in ovarian cancer mortality.

Successful fertility preservation in stage II endometrial carcinoma with long-term progestin therapy: A case report.

Progestin therapy is a fertility-sparing treatment option for well-differentiated stage IA endometrioid carcinomas without myometrial invasion. Here, we present a case of successful pregnancy and live birth following long-term progestin therapy in a patient with stage II well-differentiated endometrioid carcinoma. A 30-year-old nulliparous woman with an unremarkable medical history presented with abnormal uterine bleeding. A 45 mm mass was identified in the lower uterine segment. An endometrial biopsy revealed grade 1 endometrioid carcinoma, leading to a diagnosis of stage II uterine corpus cancer based on hysteroscopic findings. The patient refused surgical treatment and underwent oocyte retrieval and cryopreservation at another hospital. A subsequent endometrial biopsy revealed a marked reduction in the Ki-67 index from approximately 60 % to less than 10 %, suggesting the possibility of a hormone-sensitive tumor. The patient persistently refused surgery. Therefore, progestin therapy with medroxyprogesterone acetate (MPA) at a dose of 400 mg/day was initiated as a temporary measure until the patient would accept surgery. The tumor gradually reduced in size and eventually disappeared after 9 months. The MPA therapy was discontinued uneventfully after 20 months. Sixteen months after the discontinuation of MPA therapy, atypical endometrial hyperplasia was detected, and a second round of MPA therapy was initiated. Progestin retreatment was successful and was discontinued at 6 months. Four years after the initial treatment, the patient achieved pregnancy through timed intercourse and delivered a healthy baby at 38 weeks of gestation.

Cerebral infarction caused by Trousseau syndrome associated with cervical cancer.

OBJECTIVE: The combination of cancer and hypercoagulable states is often called Trousseau syndrome. In particular, cerebral infarction caused by Trousseau syndrome is reported to have a poor prognosis. In gynecology, there are many reports of ovarian cancer and a few of uterine cancer. Since there has been no comprehensive report of Trousseau syndrome in cervical cancer, we aimed to summarize Trousseau syndrome in cervical cancer. METHODS: Cerebral infarction caused by cancer-related arterial thrombosis was defined as Trousseau syndrome. Patients with cervical cancer diagnosed at our hospital between January 2014 and December 2021 were retrospectively reviewed using the hospital's medical records. RESULTS: A total of 1,432 patients were included in the study. Trousseau syndrome occurred in 6 patients (0.4%). The mean age of patients with Trousseau syndrome was 63 years (range: 53-78 years). Of the 6 patients who developed Trousseau's syndrome, 4 patients had it before or during initial treatment, and 2 during recurrent/relapsed disease treatment. The 4 patients who developed the syndrome before or during initial treatment had advanced disease: 1 in stage IIIC and 3 in stage IVB. In all cases, the disease was associated with progressive distant metastasis. The median survival time from the onset of Trousseau syndrome was 1 month (range: 0-6 months). CONCLUSION: Cervical cancer causes Trousseau syndrome in cases of advanced disease with a short time between the onset of the syndrome and mortality.

Clinical implications of the superficial uterine vein pattern for the dissection of the anterior layer of the vesicouterine ligament in radical hysterectomy.

OBJECTIVE: To describe anatomic patterns of the superficial uterine vein (sUV) and assess their association with aspects of the dissection procedure of the anterior layer of the vesicouterine ligament (aVUL) by retrospectively reviewing surgical videos. METHODS: We analyzed patients who underwent laparoscopic radical hysterectomy for early-stage cervical cancer from 2014 to 2019. The primary endpoint was the time required for aVUL dissection. Multiple linear regression analyses were performed to identify factors influencing the time required for aVUL dissection. RESULTS: Fifty-three Japanese patients were included. Two sUV configurations were observed: type 1 (the vein ran ventral to the ureter along the uterine artery) and type 2 (the vein did not run along the usual ventral course; it ran dorsal to the ureter or was absent). Approximately 30% of the sUVs were type 2. The total time for dissection of both sides of the aVUL was significantly shorter for type 2 sUVs than for type 1 sUVs. The number of hemostatic interventions during dissection of each side of the aVUL was significantly lower for type 2 sUVs than for type 1 sUVs. In the multivariate analysis, the sUV configuration was the factor significantly influencing the duration of aVUL dissection on each side (right side: ß=-143.4; left side, ß=-160.4). CONCLUSION: We demonstrated that the sUV had 2 types of courses, ventral and others, and its course affected the time required for dissection and the number of hemostatic interventions. Our results provide information supportive of improved radical hysterectomy outcomes.

Qualitative analysis of expressions used in the end-of-life discussions and their associated factors.

OBJECTIVES: Discussing end-of-life (EOL) issues with patients remains challenging for health professionals. Physicians may use various expressions, including euphemistic ones, when disclosing the prognosis to their patients to reduce their psychological impact. However, the actual expressions of EOL disclosure in clinical practice are unclear. This study aims to investigate the expressions used in EOL disclosures and explore their associated factors. METHODS: A retrospective chart review was conducted enrolling all the patients who died in a university-affiliated hospital. Expressions used in the EOL disclosure were qualitatively analyzed. The patients' participation rate and length from the discussion to death were investigated. RESULTS: EOL disclosures were observed in 341 of 358 patients. The expressions used by the physicians were categorized into 4 groups; Group 1: Clear presentation of life expectancy (n = 106; 31.1%), Group 2: Euphemistic presentation of life expectancy (n = 24; 7.0%), Group 3: Presentation of risk of sudden death (n = 147; 43.1%), Group 4: No mention on life expectancy (n = 64; 18.8%). The proportion of male patients was higher in Group 2 (79%) and lower in Group 4 (56%). Patients with cancer accounted for approximately 70% of Groups 1 and 4, but only approximately 30% of Group 3. The patient participation rate was highest in Group4 (84.4%), followed by Group 2 (50.0%). The median time from EOL disclosure to death was longer in Groups 1 and 4 (26 and 29.5 days, respectively), compared to Groups 2 and 3 (18.5 and 16 days, respectively). SIGNIFICANCE OF RESULTS: A variety of expressions are used in EOL disclosure. Patterns of communication are influenced by patients' gender and type of illness (cancer or noncancer). Euphemisms do not seem to facilitate timely disclosure of life expectancy or patient participation. For health professionals, not only devising the expressions to alleviate their patients' distress when breaking bad news but also considering the communication process and patient background are essential.

Risk-reducing decisions regarding germline BRCA pathogenic variant: focusing on the timing of genetic testing and RRSO.

BACKGROUND: In Japan, the public insurance policy was revised in 2020 to cover hereditary breast and ovarian cancer (HBOC), including genetic testing and surveillance, for patients with breast cancer (BC). Consequently, the demand for risk-reducing salpingo-oophorectomy (RRSO) has increased. This study aimed to clarify the changes in the demand and timing of genetic testing and RRSO associated with public insurance coverage for HBOC in Japan. METHODS: This retrospective analysis included 350 women with germline BRCA (gBRCA) pathogenic variants (PVs) who had visited gynaecologists; they received gBRCA genetic testing at 45.1±10.6 (20-74) years. The use of medical testing and preventive treatment was compared between the preinsurance and postinsurance groups using Mann-Whitney U and Fisher's exact tests. RESULTS: The findings indicate that RRSO rates doubled from 31.4% to 62.6% among patients with gBRCA-PV. The implementation rate was 32.4% among unaffected carriers and 70.3% among BC-affected patients. Younger patients received genetic testing with significantly shorter intervals between BC diagnosis and genetic testing and between genetic testing and RRSO. CONCLUSION: Overall, the insurance coverage for HBOC patients with BC has increased the frequency of RRSO in Japan. However, a comparison between the number of probands and family members indicated that the diagnosis among family members is inadequate. The inequality in the use of genetic services by socioeconomic groups is an issue of further concern.

Influence of dosing pattern of antipsychotics on treatment outcome of delirium in patients with advanced cancer.

BACKGROUND: Clinical guidelines recommend antipsychotics for the treatment of delirium; however, there has been no confirmed recommendation regarding their administrating patterns. This study aims to investigate whether different dosing patterns of antipsychotics (single or multiple administrations) influence the outcomes of delirium treatment. METHODS: This is a secondary analysis of a prospective observational study involving patients with advanced cancer and delirium receiving antipsychotics. The Delirium Rating Scale Revised-98 was administered at baseline and after 72 h of starting pharmacotherapy. Patients were classified into single administration group (received a single dosage within 24 h before the assessment) and multiple administration group (received more than one dosage). RESULTS: A total of 555 patients (single administration 492 (88.6%); multiple administration 63 (11.4%)) were subjected to analyses. The patients in the multiple administration group were more likely to be male, in psycho-oncology consulting settings, with lower performance status, with hyperactive delirium and with severer delirium symptoms. In the multivariate analysis, single administration was significantly associated with better improvement of delirium (p < 0.01, 95% confidence interval: 1.83-5.87) even after controlling covariates. There were no significant differences in the mean dosages of antipsychotics per day in chlorpromazine equivalent (single administration 116.8 mg/day, multiple administration 123.5 mg/day) and the incidence of adverse events between the two groups. CONCLUSIONS: In this observational study sample, Delirium Rating Scale severity score improvement in single administration was higher than that seen in multiple administration. There was no difference in adverse events between the two groups.

Impact of the coverage of risk-reducing salpingo-oophorectomy by the national insurance system for women with BRCA pathogenic variants in Japan.

To determine the impact of the coverage of risk-reducing salpingo-oophorectomy (RRSO) and mastectomy (RRM) as well as genetic testing for BRCA pathogenic variants by the national insurance system in Japan. We compared the clinical background of women who underwent RRSO at our institution before and after its coverage by the national insurance system. Those who underwent RRSO between January 2017 and December 2019 and between April 2020 and March 2022 were classified as Period. A and B, respectively. Overall, 134 women underwent RRSO during the study period. In Period A and B, 45 and 89 women underwent RRSO for the study period was 36 and 24 months, respectively. Compared with Period A, the number of women who underwent RRSO per month increased by threefold in Period B (p < 0.01). In addition, the number of women who underwent surgery for breast cancer along with RRSO increased in Period B (p < 0.01). Although the number of women who underwent concurrent RRM with RRSO in Period B increased, the difference was not statistically significant. Compared with Period A, the number of women diagnosed with BRCA pathogenic variant increased by 3.9-fold, and the proportion of women who underwent concurrent hysterectomy at the time of RRSO decreased from 66 to 7.9% in Period B (p < 0.01). Owing to the introduction of the national insurance system, the number of women who underwent RRSO and concurrent surgery for breast cancer at the time of RRSO increased in Japan.

Minimally invasive radical hysterectomy and the importance of avoiding cancer cell spillage for early-stage cervical cancer: a narrative review.

Radical hysterectomy is a standard surgery to treat early-stage uterine cervical cancer. The Laparoscopic Approach to Cervical Cancer (LACC) trial has shown that patients receiving minimally invasive radical hysterectomy have a poorer prognosis than those receiving open radical hysterectomy; however, the reason for this remains unclear. The LACC trial had 2 concerns: the learning curve and the procedural effects. Appropriate management of the learning curve effect, including surgeons' skills, is required to correctly interpret the result of surgical randomized controlled trials. Whether the LACC trial managed the learning curve effect remains controversial, based on the surgeons' inclusion criteria and the distribution of institutions with recurrent cases. An appropriate surgical procedure is also needed, and avoiding intraoperative cancer cell spillage plays an important role during cancer surgery. Cancer cell spillage during minimally invasive surgery to treat cervical cancer is caused by several factors, including 1) exposure of tumor, 2) the use of a uterine manipulator, and 3) direct handling of the uterine cervix. Unfortunately, these issues were not addressed by the LACC trial. We evaluated the results of minimally invasive radical hysterectomy while avoiding cancer cell spillage for early-stage cervical cancer. Our findings show that avoiding cancer cell spillage during minimally invasive radical hysterectomy may ensure an equivalent oncologic outcome, comparable to that of open radical hysterectomy. Therefore, evaluating the importance of avoiding cancer cell spillage during minimally invasive surgery with a better control of the learning curve and procedural effects is needed.

Moderate-Risk Genes for Hereditary Ovarian Cancers Involved in the Homologous Recombination Repair Pathway.

Approximately 20% of cases of epithelial ovarian cancer (EOC) are hereditary, sharing many causative genes with breast cancer. The lower frequency of EOC compared to breast cancer makes it challenging to estimate absolute or relative risk and verify the efficacy of risk-reducing surgery in individuals harboring germline pathogenic variants (GPV) in EOC predisposition genes, particularly those with relatively low penetrance. Here, we review the molecular features and hereditary tumor risk associated with several moderate-penetrance genes in EOC that are involved in the homologous recombination repair pathway, i.e., ATM, BRIP1, NBN, PALB2, and RAD51C/D. Understanding the molecular mechanisms underlying the expression and function of these genes may elucidate trends in the development and progression of hereditary tumors, including EOC. A fundamental understanding of the genes driving EOC can help us accurately estimate the genetic risk of developing EOC and select appropriate prevention and treatment strategies for hereditary EOC. Therefore, we summarize the functions of the candidate predisposition genes for EOC and discuss the clinical management of individuals carrying GPV in these genes.

Beliefs and Perceptions About Parenteral Nutrition and Hydration by Advanced Cancer Patients.

Background: The beliefs and perceptions of parenteral nutrition and hydration (PNH) by advanced cancer patients have not been elucidated. Objectives: To clarify their beliefs and perceptions and to explore the relationships between their beliefs and perceptions and cachexia stages. Design/setting/subjects: A questionnaire survey of advanced cancer patients receiving palliative care across Japan. Measurements: We asked patients to answer 15 items regarding their beliefs and perceptions of PNH. Frequencies were calculated for the patient characteristics and survey parameters. Comparisons were performed using the Mann-Whitney U test. We conducted a factor analysis and a multiple logistic regression analysis to identify the independent factors affecting cancer cachexia stages. Results: Among 495 patients, 378 responded. Due to missing data, 357 remained in the frequency distribution analysis, and 344 were classified into the noncachexia group (n = 174) and cachexia group (n = 170). Approximately 60% thought that PNH were beneficial. Approximately 70% considered PNH a standard medical practice. Approximately 70% did not feel that they received a sufficient explanation. There were no significant differences in any items between the two groups. We extracted four conceptual groups. The concept of "Belief that PNH are harmful" was identified as an independent factor [odds ratio 2.57 (95% confidence intervals 1.10-6.01), p = 0.030]. Conclusion: More than half of the patients thought that PNH were beneficial and standard medical practices with or without cancer cachexia. The negative perception of PNH decreased in patients with cancer cachexia.

Prevalence of Pathogenic Germline BRCA1/2 Variants and Their Association with Clinical Characteristics in Patients with Epithelial Ovarian Cancer in a Rural Area of Japan.

The prevalence of germline BRCA1 or BRCA2 pathogenic variants (gBRCA1/2-PV) in patients with primary epithelial ovarian cancer (OC) in a rural area of Japan and their association with clinical characteristics, including treatment response and survival outcome, were investigated. A total of 123 unbiased patients with OC were tested for gBRCA1 and gBRCA2 using next-generation sequencing-based targeted amplicon sequencing. Clinical characteristics of OC patients with and without gBRCA1/2 status were compared. The overall prevalence of gBRCA1/2-PV was 15.4% (19 cases), with gBRCA2-PV (10.5%, 13 cases) being more common than gBRCA1-PV (4.9%, 6 cases). Among the observed gBRCA1/2-PV, several novel variants were included, suggesting that gBRCA1/2-PV unique to the local area exist. gBRCA1/2-PV was significantly more prevalent in OC patients at an older age, with high-grade serous carcinoma, with advanced-stage tumors, and with a family history of breast cancer or hereditary breast and ovarian cancer syndrome (HBOC)-associated cancers. Patients with advanced-stage OC with gBRCA1/2-PV showed a significantly lower recurrence rate and tended to have better progression-free and overall survival than those with wild-type gBRCA1/2. Genetic testing for gBRCA1/2 status in all OC patients is useful not only for diagnosing HBOC in patients and their relatives to assess the risk of HBOC-associated cancers, but also to estimate therapy response and outcomes in patients.

Clinical Management of Atypical Endometrial Cells of Undetermined Significance Followed by Negative Cytology.

INTRODUCTION: In Japan, endometrial cytology is widely performed to evaluate the status of the endometrium in women with suspected endometrial cancer. A new classification system for endometrial cytology has recently been used: the Yokohama system, based on a descriptive reporting format. This study aimed to clarify the triage for patients with atypical endometrial cells of undetermined significance (ATEC-US) when followed by negative endometrial cytology. METHODS: We enrolled patients diagnosed with ATEC-US at the Cancer Institute Hospital between January 2016 and December 2017, based on the following inclusion criteria: (1) ATEC-US diagnosed by office endometrial cytology, with or without office endometrial biopsy; (2) follow-up endometrial cytology was performed 3-6 months after initial sampling, with a negative result for malignancy; and (3) no prior history of conservative treatment with progestin for endometrial cancer or atypical endometrial hyperplasia (ATEC-A). Among eligible patients, we analyzed those later diagnosed by endometrial biopsy with ATEC-A or carcinoma. RESULTS: Among 187 patients, 65 met the inclusion criteria. Forty-two patients (64.6%) were observed for more than 24 months. Two patients (3.1%) developed ATEC-A during a median observation time of 26.5 months; the times to diagnosis were 32 months and 22 months. DISCUSSION/CONCLUSION: No patient developed ATEC-A or worse within 1 year. For patients with ATEC-US, if negative cytology is obtained at the next examination, a close follow-up is not necessary.

Extreme leanness, lower skeletal muscle quality, and loss of muscle mass during treatment are predictors of poor prognosis in cervical cancer treated with concurrent chemoradiation therapy.

BACKGROUND: Human papillomavirus vaccination is not widespread in Japan, and the low screening rates result in many cases of locally advanced cervical cancer. We investigated the prognostic significance of sarcopenia in patients with cervical cancer to guide healthcare policies to improve treatment outcomes. METHODS: This retrospective study included 83 patients with cervical cancer without distant metastasis who underwent primary concurrent chemoradiotherapy between 2013 and 2018. We analyzed the indicators of physical condition and muscle quantity using the SYNAPSE VINCENT software. Muscle mass and the relationship between treatment toxicity and prognosis were evaluated. RESULTS: The patients' median age was 60 (range 33‒80) years. Cancer stage distribution was as follows: cT2b or higher, 84.3%; N1, 65.1%; and MA, 27.7%. The overall sarcopenia (skeletal muscle index [SMI] < 38.5) rate was 30.1%, and the rate was 33.9 and 22.2% in patients aged < 64 and ≥ 65 years, respectively. No correlation was observed between clinical stage and musculoskeletal indices. Treatment resulted in decreased body weight and SMI; after treatment, the sarcopenia rate increased to 37.3%. A higher intramuscular adipose tissue content (IMAC) reduced the number of chemotherapy cycles needed. Treatment-associated SMI decreases of ≥ 7% indicated poor prognosis, with significant differences in progression-free survival and overall survival (p = 0.013 and p = 0.012, respectively). Patients who were very lean (body mass index < 18.5 kg/m2) before treatment had a poor prognosis (p = 0.016 and p < 0.001). CONCLUSIONS: Our findings emphasize the importance of assessing original nutritional status and maintaining muscle mass and quality during the treatment of patients with cervical cancer.

Patient participation and associated factors in the discussions on do-not-attempt-resuscitation and end-of-life disclosure: a retrospective chart review study.

BACKGROUND: Patient participation is a key foundation of advance care planning (ACP). However, a patient himself/herself may be left out from sensitive conversations such as end-of-life (EOL) care discussions. The objectives of this study were to investigate patients' participation rate in the discussion of Cardiopulmonary Resuscitation (CPR) / Do-Not-Attempt-Resuscitation (DNAR) order, and in the discussion that the patient is at his/her EOL stage (EOL disclosure), and to explore their associated factors. METHODS: This is a retrospective chart review study. The participants were all the patients who were hospitalized and died in a university-affiliated teaching hospital (tertiary medical facility) in central Tokyo, Japan during the period from April 2018 to March 2019. The following patients were excluded: (1) cardiopulmonary arrest on arrival; (2) stillbirth; (3) under 18 years old at the time of death; and (4) refusal by their bereaved family. Presence or absence of CPR/DNAR discussion and EOL disclosure, patients' involvement in those discussions, and their associated factors were investigated. RESULTS: CPR/DNAR discussions were observed in 336 out of the 358 patients (93.9%). However, 224 of these discussions were carried out without a patient (patient participation rate 33.3%). Male gender (odds ratio (OR) = 2.37 [95% confidence interval (CI) 1.32-4.25]), living alone (OR = 2.51 [1.34-4.71]), and 1 year or more from the date of diagnosis (OR = 1.78 [1.03-3.10]) were associated with higher patient's participation in CPR/DNAR discussions. The EOL disclosure was observed in 341 out of the 358 patients (95.3%). However, 170 of the discussions were carried out without the patient (patient participation rate 50.1%). Patients who died of cancer (OR = 2.41[1.45-4.03]) and patients without mental illness (OR=2.41 [1.11-5.25]) were more likely to participate in EOL disclosure. CONCLUSIONS: In this clinical sample, only up to half of the patients participated in CPR/DNAR discussions and EOL disclosure. Female, living with family, a shorter period from the diagnosis, non-cancer, and mental illness presence are risk factors for lack of patients' participation in CPR/DNAR or EOL discussions. Further attempts to facilitate patients' participation, based on their preference, are warranted.

Minimum environmental enrichment is effective in activating antitumor immunity to transplanted tumor cells in mice.

Studies of environmental enrichment are progressing in the fields of nervous system, stress and exercise. Recently, housing in enriched environment have shown to influence to carcinogenesis and life span. However, the study for antitumor effect of environmental enrichment are difficult to reproduce due to the complexity of the experimental technique. Thus, a simpler experiment system is needed for antitumor study using environmental enrichment. In this research, we propose a minimum environmental enrichment, which is an experimental system by placing one mouse igloo which is normally used as a mouse shelter in the rearing environment. The experimental system of minimum environmental enrichment is not only easy to reproduce but also have enhanced activity to suppress the growth of transplanted tumor significantly. It was found that the activation of NK cells is involved also in the immune system related to tumor immunity of minimum environmental enrichment. Because minimum environmental enrichment is effective in activating antitumor immunity to transplanted tumor cells in mice, we believe this will be useful for promoting antitumor studies using environmental enrichment.

Resveratrol suppresses proliferation and induces apoptosis of uterine sarcoma cells by inhibiting the Wnt signaling pathway.

Resveratrol, a natural product and peroxisome proliferator-activated receptor (PPAR) agonist, has been reported to exert anti-cancer effects in several tumor models. A previous study by our group reported that prostaglandin J2, a PPARγ ligand, inhibited cell proliferation in a uterine sarcoma cell line. The aim of the present study was to investigate the role of the Wnt signaling pathway in resveratrol-induced apoptosis and inhibition of cell proliferation in the MES-SA human uterine sarcoma cell line. A WST-1 assay demonstrated that resveratrol inhibited cell proliferation in the MES-SA cell line, and flow cytometry revealed that the number of apoptotic cells increased in a resveratrol dose-dependent manner. The mechanisms underlying these effects of resveratrol were speculated to involve the expression of ß-catenin and its target gene, c-myc, which were examined using western blot analysis. The results revealed a dose-dependent downregulation of this ß-catenin and c-myc. This effect was blunted by a pharmacological inhibitor of glycogen synthase kinase 3ß. Therefore, it is likely that resveratrol inhibited the cell proliferation and increased the number of apoptotic cells, at least partially, via the Wnt signaling pathway. The present results suggest that resveratrol is a potential candidate for the treatment of uterine sarcoma.