Background: Poly (adenosine diphosphate)-ribose polymerase (PARP) inhibitors for tumors with homologous recombination deficiency (HRD), including pathogenic mutations in BRCA1/2, have been developed. Genomic analysis revealed that about 20% of uterine leiomyosarcoma (uLMS) have HRD, including 7.5%–10% of BRCA1/2 alterations and 4%–6% of carcinomas of the uterine corpus, and 2.5%–4% of the uterine cervix have alterations of BRCA1/2. Preclinical and clinical case reports suggest that PARP inhibitors may be effective against those targets. The Japanese Gynecologic Oncology Group (JGOG) is now planning to conduct a new investigator-initiated clinical trial, JGOG2052. Methods JGOG2052 is a single-arm, open-label, multi-center, phase 2 clinical trial to evaluate the efficacy and safety of niraparib monotherapy for a recurrent or persistent rare fraction of gynecologic malignancies with BRCA1/2 mutations except for ovarian cancers. We will independently consider the effect of niraparib for uLMS or other gynecologic malignancies with BRCA1/2 mutations (cohort A, C) and HRD positive uLMS without BRCA1/2 mutations (cohort B). Participants must have 1–3 lines of previous chemotherapy and at least one measurable lesion according to RECIST (v.1.1). Niraparib will be orally administered once a day until lesion exacerbation or unacceptable adverse events occur. Efficacy will be evaluated by imaging through an additional computed tomography scan every 8 weeks. Safety will be measured weekly in cycle 1 and every 4 weeks after cycle 2 by blood tests and physical examinations. The sample size is 16–20 in each of cohort A and B, and 31 in cohort C. Primary endpoint is the objective response rate.

Objectives: This review aims to introduce preoperative scoring systems to predict lymph node metastasis (LNM) and ongoing clinical trials to investigate the therapeutic role of lymphadenectomy for endometrial cancer. Methods: We summarized previous reports on the preoperative prediction models for LNM and evaluated their validity to omit lymphadenectomy in our recent cohorts. Next, we compared characteristics of two ongoing lymphadenectomy trials (JCOG1412, ECLAT) to examine the survival benefit of lymphadenectomy in endometrial cancer, and described the details of JCOG1412. Results: Lymphadenectomy has been omitted for 64 endometrial cancer patients who met lowrisk criteria to omit lymphadenectomy using our scoring system (LNM score) and no lymphatic failure has been observed. Other two models also produced comparable results. Two randomized phase III trials to evaluate survival benefit of lymphadenectomy are ongoing for endometrial cancer. JCOG1412 compares pelvic lymphadenectomy alone with pelvic and para-aortic lymphadenectomy to evaluate the therapeutic role of para-aortic lymphadenectomy for patients at risk of LNM. For quality assurance of lymphadenectomy, we defined several regulations, including lower limit of the number of resected nodes, and submission of photos of dissected area to evaluate thoroughness of lymphadenectomy in the protocol. The latest monitoring report showed that the quality of lymphadenectomy has been well-controlled in JCOG1412. Conclusion Our strategy seems reasonable to omit lymphadenectomy and could be generalized in clinical practice. JCOG1412 is a high-quality lymphadenectomy trial in terms of the quality of surgical procedures, which would draw the bona-fide conclusions regarding the therapeutic role of lymphadenectomy for endometrial cancer.

A 46-year-old man who had been hospitalized for treatment of pneumonia was referred to our hospital with a diagnosis of acute pulmonary thromboembolism. Multi-detector row computed tomography revealed massive thrombi in the bilateral main pulmonary arteries. Transthoracic echocardiography showed dilated right heart chambers and a large floating thrombus in the right atrium. Emergency thromboembolectomy was performed. Although fresh thrombi were removed from the right atrium and left main pulmonary artery, organized old thrombi were present in the bilateral pulmonary arteries, leading to a diagnosis of chronic thromboembolic pulmonary hypertension. Because no instruments were available for pulmonary endarterectomy, the surgery was terminated with percutaneous cardiopulmonary support. Five days postoperatively, pulmonary endarterectomy was performed under deep hypothermic circulatory arrest. The postoperative course was uneventful, and the patient returned to his preoperative lifestyle without the need for oxygen support.

A 46-year-old man who developed fever and general fatigue was referred to our hospital with suspicion of infective endocarditis. A ventricular septal defect had been previously diagnosed. Transthoracic echocardiography revealed vegetation on the aortic, mitral, and pulmonary valves, and each valve had significant regurgitation. An emergency operation was performed because of congestive heart failure. The aortic and mitral valves were replaced with mechanical valves. The pulmonary valve was repaired ; the anterior leaflet was resected and replaced by glutaraldehyde-treated autologous pericardium. The patient's postoperative course was uneventful. Recurrence of infection was not observed for 3 years after the operation. Triple-valve endocarditis, especially that involving a combination of the aortic, mitral, and pulmonary valves, is rare. Involvement of multiple valves on both sides of the heart may be attributed to a congenital intracardiac shunt. Early surgical intervention may be useful to control infection and heart failure, as in the present case.

Objective: Adequate periconceptional intake of folic acid decreases the risk of neural tube defects of infant. The present study aimed to investigate the awareness of nursing students about the importance of folic acid intake for the prevention of neural tube defects.Design: Questionnaire survey.Methods: A self-administered questionnaire regarding the importance of folic acid intake for the prevention of neural tube defects was distributed to 423 nursing students of Tohoku University and Tohoku Fukushi University.Results: Among the 408 respondents (response rate; 96.5%), 129 (31.6%) nursing students were aware that folic acid intake decreases the risk of neural tube defects. In the multivariate logistic regression analysis, grade 3-4 (odds ratio = 11.779, 95% confident interval = 5.739-24.177) were associated with the awareness of the importance of folic acid intake among nursing students. Of 129 nursing students who recognized the importance of folic acid intake, 52 (40.3%) and 11 (8.5%) recognized that women should begin folic acid intake before conception and should take about 400μg of folic acid per day during pregnancy respectively.Conclusion: About 30% of nursing students recognized that folic acid intake decreases the risk of neural tube defects and many did not know the details of the effective intake for the prevention of neural tube defects. Therefore, more aggressive promotion of the awareness of the importance of folic acid intake among nursing students is warranted.

Objective: Adequate periconceptional folic acid intake decreases the risk of neural tube defects in infants.  The present study aimed to investigate the awareness of pharmacy students regarding the importance of folic acid intake for the prevention of neural tube defects.
Design: Questionnaire survey.
Methods: A self-administered questionnaire regarding the importance of folic acid intake for the prevention of neural tube defects was distributed to 750 pharmacy students at Tohoku and Ohu Universities.
Results: Among the 685 respondents (response rate; 91.3%), 74 (10.8%) were aware that folic acid intake decreases the risk of neural tube defects.  In multivariate logistic regression analysis, awareness of the importance of folic acid intake was evident among 5th- and 6th-year pharmacy students (odds ratio=3.352, 95% confidence interval=1.797-6.253) and among those who used dietary supplements (2.275, 1.306-3.966).  Among the 74 pharmacy students who recognized the importance of folic acid intake, 17 (23.0%) and 3 (4.1%) were aware that women should begin taking a folic acid supplement before conception and should take about 400 μg per day during pregnancy, respectively.
Conclusion: Only about 10% of the pharmacy students in this study recognized that folic acid intake decreases the risk of neural tube defects, and many were unaware of the recommended intake amount.  Therefore, awareness of the importance of folic acid intake must be more aggressively promoted among pharmacy students.

Objective: The water-soluble extract of Ganoderma lucidum mycelia (WER), which is used as a health food, reduced hyperglycemia and enhanced glucose transporter 4 (GLUT4) translocation to the plasma membrane in skeletal muscle and adipose tissue in KK-A^y mice, a type 2 diabetic animal model with obesity.In order to elucidate the reduction of hyperglycemia by WER, we investigated the translocation of glucose transporter 4, glucose uptake and associating signal transduction in rat skeletal muscle (L6) cells. Method: The glucose uptake was analyzed with radioactive 2-deoxy-D-glucose.The localization of GLUT4 in L6 cells treated with various concentrations of WER was analyzed with immunohistochemical staining and Western blot technique.As a positive control, insulin or troglitazone was used in these experiments.Furthermore, the activation of intracellular signaling pathways by Western blot analysis and the influence of glucose uptake using four kinds of inhibitors (LY294002 as potent PI3K inhibitor, rapamycin as mTOR inhibitor, Gö6983 as broad PKC inhibitor, compound C as AMPK inhibitor) was evaluated. Results: GLUT4 protein content in the plasma membrane was induced in a dose-dependent manner of WER without increasing the gene expression and amount of total protein in the L6 cells and the glucose uptake was augmented with increasing the amount of GLUT4 translocated on the plasma membrane.The phosphorylation of phosphatidylinositol-3 kinase (PI3K), Akt and acetyl CoA carboxylase (ACC) were induced in a concentration dependent manner and inhibited by the above inhibitors except rapamycin. Conclusion: These results indicate that the hypoglycemic effect of some material(s) in WER may be due to the enhancement of glucose uptake through GLUT4 translocation on the plasma membrane by activating the PI3K/Akt pathway through improving insulin resistance.

Objective: Recently, we reported that long-term intake of a water-soluble extract from culture medium of Ganoderma lucidum mycelia (WER) reduced hyperglycemia and enhanced glucose transporter-4 (GLUT4) translocation to the plasma membrane in skeletal muscles and adipose tissue in KK-A^y mice, a type 2 diabetic animal model with obesity. In the present study, we investigated the effect of WER on hepatic carbohydrate metabolism.
Methods: Female KK-A^y mice were given free access to water and high-fat food containing 0.5% WER for 8 weeks, and blood glucose levels were assessed every week. At the end of the experimental period, the expression and activities of sugar metabolic enzymes in the liver were determined by Real Time RT-PCR and each activity measurement method. Also, the amount of glycogen was measured by anthrone-sulfuric acid method. Furthermore, the expression level of GLUT2 and activation of AMP kinase (AMPK) and glycogen synthase kinase 3β (GSk3β) was also determined by western blot analysis.
Results: The mice with the high-fat ingestion showed a gradual increase in the levels of blood glucose and body weight. In the WER-treated mice, the blood glucose level was suppressed after 2 weeks of intake. The gene expression and enzyme activities of both glucose-6-phosphatase and phosphoenolpyruvate carboxykinase were suppressed, whereas those of glucokinase were increased in the mice with WER intake and pioglitazone administration. The accumulation of glycogen was increased. Moreover the expression of GLUT2 and phosphorylation levels of AMPK and GSk3β were also increased in the mice with WER intake.
Conclusion: These results indicate that WER affects hepatic carbohydrate metabolism, which may derive from the suppression of gluconeogenesis through the modulation of related enzymes and enhancement of glucose uptake, glycolysis and glycogen synthesis.

High-dose methotrexate-based chemotherapy has extended survival in patients with primary central nervous system lymphoma (PCNSL). However, although salvage treatment is necessary in recurrent and refractory PCNSL, this has not been standardized. We herein describe the efficacy of a combination of rituximab and temozolomide (TMZ) in two consecutive patients with recurrent and refractory PCNSL. Based on the immunohistochemical study, case 1 had a non-germinal center B-cell-like (non-GCB) subtype, was positive for bcl-2 and negative for O6-methylguanine-DNA methyltransferase (MGMT). Case 2 was GCB subtype, bcl-2-, and MGMT+. Because of the positive expression of MGMT, interferon-beta was additionally given in case 2. Complete responses and partial responses were obtained after the third and fourth cycles of combination therapy, respectively. This was maintained for 12 months, with acceptable toxicity. The combination of rituximab and TMZ was effective in tumors with different immunohistochemical profiles. This combination therapy warrants further study in a larger population.
Aged ; Antibodies, Monoclonal, Murine-Derived/*therapeutic use ; Antineoplastic Agents/*therapeutic use ; Central Nervous System Neoplasms/*drug therapy ; Dacarbazine/*analogs & derivatives/therapeutic use ; Drug Therapy, Combination/*methods ; Humans ; Lymphoma/*drug therapy ; Male ; Middle Aged ; Neoplasm Recurrence, Local/drug therapy

Objective: Ganoderma lucidum (Rei-shi) is widely used as an alternative medicine agent to promote health and longevity. The water-soluble extract from culture medium of Ganoderma lucidum mycelia (WER) is prepared from a solid medium composed of bagasse and rice bran overgrown for 3–4 months with Ganoderma lucidum mycelia.
Design: In this study, we evaluate antioxidant activity of WER in vitro, and examined the effects of oral treatment of WER on oxidative stress in streptozotocin (STZ)-induced diabetic mice.
Method: Male ICR mice were treated with STZ (150 mg/kg, i.p.) and were housed for a week for induction of experimental diabetic state. WER (1 g/kg daily) was orally administered for an additional 9 weeks, and the levels of blood glucose, oxidative stress in plasma, liver and kidney of the mice were assessed.
Result: WER inhibited generation of superoxide anion and lipid peroxidation in concentration dependent manner in vitro. Oral administration of WER to diabetic mice significantly reduced the levels of blood glucose, hydroperoxides, triglyceride, ALT, and AST. Moreover, WER prevented the increase in lipid peroxide levels and the decrease in activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) in liver and kidney of diabetic mice. In addition, histochemical studies revealed that treatment of WER precluded the sinusoidal dilation in liver and expansion of mesangial matrix in kidney of diabetic mice. Normal mice treated with WER showed no change in any parameters studied.
Conclusion: These data suggested that WER can act as an antioxidant in vivo, and show the antidiabetic effects by relieving diabetic hyperglycemia-induced oxidative stress.