Serum Prognostic Factors of Androgen-deprivation Therapy Among Japanese Men With De Novo Metastatic Prostate Cancer.

BACKGROUND/AIM: To date, several serum prognostic factors have been reported in metastatic prostate cancer. In this study, we examined the prognostic value of these serum markers in Japanese men. PATIENTS AND METHODS: This study included 104 patients with metastatic prostate cancer who were treated with primary androgen-deprivation therapy from 2001 to 2013. Clinicopathological factors including several serum markers were investigated for association with progression-free (PFS) and overall (OS) survival. RESULTS: During a median follow-up of 48.1 months, median PFS and OS were 24.0 months and 67.4 months, respectively. When adjusted by age, prostate-specific antigen at diagnosis, Gleason score, and clinical stage, serum lactate dehydrogenase value was significantly associated with PFS [hazard ratio (HR)=1.42, 95% confidence interval (CI)=1.15-1.74; p=0.0004] and OS (HR=1.46, 95% CI=1.13-1.82; p=0.0014), in addition to alkaline phosphatase value for OS (HR=1.04; 95% CI=1.00-1.07; p=0.015). CONCLUSION: This study demonstrates the prognostic significance of alkaline phosphatase and lactate dehydrogenase values in Japanese men with de novo metastatic hormone-sensitive prostate cancer.

Transition of Spleen Volume Long After Pediatric Living Donor Liver Transplantation for Biliary Atresia.

PURPOSE: After undergoing the Kasai procedure for biliary atresia (BA), most patients develop severe splenomegaly that tends to be improved by liver transplantation. However, fluctuations in splenic volume long after transplantation remain to be elucidated. PATIENTS AND METHODS: Seventy-one consecutive patients who had undergone pediatric living donor liver transplantation (LDLT) for BA were followed up in our outpatient clinic for 5 years. They were classified into 3 groups according to their clinical outcomes: a good course group (GC, n = 41) who were maintained on only 1 or without an immunosuppressant, a liver dysfunction group (LD, n = 18) who were maintained on 2 or 3 types of immunosuppressants, and a vascular complication group (VC, n = 11). Splenic and hepatic volumes were calculated by computed tomography in 464 examinations and the values compared before and after the treatment, especially in the VC group. RESULTS: Splenic volume decreased exponentially in the GC group, with splenic volume to standard spleen volume ratio (SD) being 1.59 (0.33) 5 years after liver transplantation. Splenic volume to standard spleen volume ratios were greater in the VC and LD groups than in the GC group. Patients in the VC group with portal vein stenosis developed liver atrophy and splenomegaly, whereas those with hepatic vein stenosis developed hepatomegaly and splenomegaly. Interventional radiation therapy tended to improve the associated symptoms. CONCLUSIONS: Fluctuations in splenic volume long after pediatric LDLT for BA may reflect various clinical conditions. Evaluation of both splenic and hepatic volumes can facilitate understanding clinical conditions following pediatric LDLT.

Antibody Drug Treatment for Steroid-Resistant Rejection After Pediatric Living Donor Liver Transplantation: A Single-Center Experience.

BACKGROUND: Antibody drugs have been used to treat steroid-resistant rejection (SRR) after liver transplantation. Although anti-thymocyte globulin has been used for SRR after liver transplantation in place of muromonab-CD3 since 2011 in Japan, the effectiveness of anti-thymocyte globulin after pediatric living-donor liver transplantation (LDLT) has not yet been reported. The aim of this study was to evaluate the effectiveness of antibody drug treatment for SRR after pediatric LDLT in our single center. METHODS: Between May 2001 and December 2013, 220 pediatric LDLTs were performed. Initial immunosuppression after LDLT included tacrolimus and methylprednisolone therapy. Acute rejection was diagnosed by use of a liver biopsy and the administration of steroid pulse treatment, and SRR was defined as acute rejection refractory to the steroid pulse treatment. RESULTS: Acute rejection and SRR occurred in 74 (33.6%) and 16 patients (7.3%), respectively. The graft survival rates of non-SRR and SRR were 92.4% and 87.5%, respectively (P = .464). The median concentration of alanine aminotransferase before and after the administration of antibody drug was 193.5 mU/mL (range, 8-508) and 78 mU/mL (range, 9-655), respectively (P = .012). The median rejection activity index before and after the administration of antibody drugs was 5 (range, 2-9) and 1 (range, 0-9), respectively (P = .004). After antibody drug treatment, 12 patients had cytomegalovirus infections, 2 patients had Epstein-Barr virus infections, 3 patients had respiratory infections, and 1 patient had encephalitis. The cause of death in 1 patient with SRR was recurrence of infant fulminant hepatic failure. CONCLUSIONS: Antibody drug treatment for SRR after pediatric LDLT is safe and effective.

Simulation training for medical emergencies in the dental setting using an inexpensive software application.

INTRODUCTION: Every dental provider needs to be educated about medical emergencies to provide safe dental care. Simulation training is available with simulators such as advanced life support manikins and robot patients. However, the purchase and development costs of these simulators are high. We have developed a simulation training course on medical emergencies using an inexpensive software application. The purpose of this study was to evaluate the educational effectiveness of this course. MATERIALS AND METHODS: Fifty-one dental providers participated in this study from December 2014 to March 2015. Medical simulation software was used to simulate a patient's vital signs. We evaluated participants' ability to diagnose and treat vasovagal syncope or anaphylaxis with an evaluation sheet and conducted a questionnaire before and after the scenario-based simulation training. RESULTS: The median evaluation sheet score for vasovagal syncope increased significantly from 7/9 before to 9/9 after simulation training. The median score for anaphylaxis also increased significantly from 8/12 to 12/12 (P < .01). For the item "I can treat vasovagal syncope/anaphylaxis adequately," the percentage responding "Strongly agree" or "Agree" increased from 14% to 56% for vasovagal syncope and from 6% to 42% for anaphylaxis with simulation training. CONCLUSIONS: This simulation course improved participants' ability to diagnose and treat medical emergencies and improved their confidence. This course can be offered inexpensively using a software application.

Impact of histone demethylase KDM3A-dependent AP-1 transactivity on hepatotumorigenesis induced by PI3K activation.

Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation. Particularly, the expression of Cd44, a liver cancer stem marker, was regulated by AP-1 in a Kdm3a-dependent manner. We identified Cd44-positive hepatocytes with epithelial-mesenchymal transition-related expression profiles in the Pik3ca Tg liver and confirmed their in vivo tumorigenic capacity. Notably, the number and tumor-initiating capacity of Cd44-positive hepatocytes were governed by Kdm3a. As a mechanism in Kdm3a-dependent AP-1 transcription, Kdm3a recruited c-Jun to the AP-1 binding sites of Cd44, Mmp7 and Pdgfrb without affecting c-Jun expression. Moreover, Brg1, a component of the SWI/SNF chromatin remodeling complex, interacted with c-Jun in a Kdm3a-dependent manner and was bound to the AP-1 binding site of these genes. Finally, KDM3A and c-JUN were co-expressed in 33% of human premalignant lesions with PI3K activation. Our data suggest a critical role for KDM3A in the PI3K/AP-1 oncogenic axis and propose a novel strategy for inhibition of KDM3A against liver tumor development under PI3K pathway activation.

Total internal biliary diversion during liver transplantation for type 1 progressive familial intrahepatic cholestasis: a novel approach.

LT for PFIC type 1 is often complicated by postoperative diarrhea and recurrent graft steatosis. A 26-month-old female child with cholestatic jaundice, pruritus, diarrhea, and growth retardation revealed total bilirubin 9.1 mg/dL, gamma-glutamyl transpeptidase 64 IU/L, and TBA 295.8 µmol/L. Genetic analysis confirmed ATP8B1 defects. A LT (segment 2, 3 graft) from the heterozygous father was performed. Biliary diversion was performed by a 35-cm jejunum conduit between the graft hepatic duct and the mid-transverse colon. Stools became pigmented immediately. Follow-up at 138 days revealed resolution of jaundice and pruritus and soft-to-hard stools (6-8 daily). Radioisotope hepato-biliary scintigraphy (days 26, 68, and 139) confirmed unobstructed bile drainage into the colon (t1/2 34, 27, and 19 minutes, respectively). Contrast meal follow-through at day 62 confirmed the absence of any colo-jejuno-hepatic reflux. At 140 days, contrast follow-through via the biliary stent revealed patent jejuno-colonic anastomosis and satisfactory transit. Graft biopsy at LT, 138 days, and 9 months follow-up revealed comparable grades of macrovesicular steatosis (<20%). TIBD during LT may be a clinically effective stoma-free biliary diversion and may prevent recurrent graft steatosis following LT for PFIC type 1.

Living-Donor Liver Transplantation Using Segment 2 Monosegment Graft: A Single-Center Experience.

BACKGROUND: In small infants, left lateral segment grafts are sometimes too large to overcome the problems of large-for-size grafts in the abdominal compartment. To address this problem, we have developed a safe living donor graftectomy for neonates, a so-called "S2 monosegment graft" to minimize graft thickness. We reviewed our single-center experience to evaluate the feasibility of this technique for reducing graft size. METHODS: Eleven living-donor liver transplants using S2 monosegment grafts were performed between October 2008 and September 2014 at our institution. Medical records of both donors and recipients were reviewed and data collected retrospectively. RESULTS: The mean age of recipients at the time of transplantation was 125.3 days, including 3 neonates. The average S2 monosegment graft weight was 127.4 g, and the graft-to-recipient body weight ratio was successfully reduced to 3.5%. The graft livers were reduced to 4.1 cm in thickness. Two recipients with grafts larger than 5 cm could not undergo primary abdominal closure. Portal vein stenosis and biliary stenosis was observed in 1 recipient, and hepatic artery complications were seen in 2 recipients; the clinical course for all donors were uneventful. Liver regeneration was seen in every patient. The graft and patient 1-year survival rate was 100%. CONCLUSIONS: Living-donor liver transplantation using S2 monosegment grafts offers a safe and useful option for treating smaller infants. Here, we introduce our method of S2 monosegment graft emphasizing the donor harvest and graft thickness.

Effects of rotational acetabular osteotomy on the mechanical stress within the hip joint in patients with developmental dysplasia of the hip: a subject-specific finite element analysis.

In this study we used subject-specific finite element analysis to investigate the mechanical effects of rotational acetabular osteotomy (RAO) on the hip joint and analysed the correlation between various radiological measurements and mechanical stress in the hip joint. We evaluated 13 hips in 12 patients (two men and ten women, mean age at surgery 32.0 years; 19 to 46) with developmental dysplasia of the hip (DDH) who were treated by RAO. Subject-specific finite element models were constructed from CT data. The centre-edge (CE) angle, acetabular head index (AHI), acetabular angle and acetabular roof angle (ARA) were measured on anteroposterior pelvic radiographs taken before and after RAO. The relationship between equivalent stress in the hip joint and radiological measurements was analysed. The equivalent stress in the acetabulum decreased from 4.1 MPa (2.7 to 6.5) pre-operatively to 2.8 MPa (1.8 to 3.6) post-operatively (p < 0.01). There was a moderate correlation between equivalent stress in the acetabulum and the radiological measurements: CE angle (R = -0.645, p < 0.01); AHI (R = -0.603, p < 0.01); acetabular angle (R = 0.484, p = 0.02); and ARA (R = 0.572, p < 0.01). The equivalent stress in the acetabulum of patients with DDH decreased after RAO. Correction of the CE angle, AHI and ARA was considered to be important in reducing the mechanical stress in the hip joint.

Natural history of bleeding risk in colonic diverticulosis patients: a long-term colonoscopy-based cohort study.

BACKGROUND: The natural history of bleeding risk from colonic diverticulosis remains unclear. AIM: To identify the incidence of bleeding in colonic diverticulosis patients and associated risk factors. METHODS: A cohort of 1514 patients with colonoscopy-confirmed asymptomatic diverticulosis was selected between 2001 and 2013. Age, sex and location of colonic diverticulosis (right or left side, or bilateral) were assessed. The endpoint was a bleeding event, and data were censored at the time of last colonoscopy. The cumulative and overall incidences of bleeding were estimated using the Kaplan-Meier and person-years methods. The Cox proportional hazards model was used to estimate age- and sex-adjusted hazard ratios (aHRs). RESULTS: The median follow-up period was 46 months. Bleeding events occurred in 35 patients, and the median time-to-event interval was 50 months. Kaplan-Meier analysis showed that the cumulative incidence of diverticular bleeding was 0.21% at 12 months, 2.2% at 60 months and 9.5% at 120 months. By the person-years method, the overall incidence rate of bleeding was 0.46 per 1000 patient-years. On multivariate analysis, age ≥70 (aHR. 3.7) and bilateral diverticulosis (aHR, 2.4) were significant risk factors for bleeding. CONCLUSIONS: This long-term follow-up study demonstrated that the cumulative incidence of bleeding from diverticulosis was approximately 2% at 5 years and 10% at 10 years, and the overall incidence was 0.46 per 1000 patient-years. Bilateral diverticulosis increased the risk of bleeding.

Uterine endometrial carcinoma with trophoblastic differentiation: a case report with literature review.

Choriocarcinoma is categorized as either gestational or nongestational depending on its origin. Nongestational choriocarcinoma originated in the trophoblastic differentiation is a rare but an aggressive tumor. This article reports a nongestational case of a uterine endometrial carcinoma with trophoblastic differentiation. A 54-year-old woman with a history of atypical genital bleeding that underwent semi-radical hysterectomy, bilateral salpingo-oophrectomy, and pelvic lymph nodes dissection. Pathological investigation showed that the tumor had endometrioid adenocarcinoma and choriocarcinomatous components. Although a series of multimodality treatments including craniotomy were performed, she died of aggressive lung and brain metastases one year after the primary surgery.

First case report of de novo ulcerative colitis developing after orthotopic liver transplantation successfully treated by granulocyte and monocyte apheresis.

BACKGROUND: Immunosuppressants such as tacrolimus and cyclosporine are prescribed long-term after orthotopic liver transplantation (OLT) to prevent allograft rejection. Although these immunosuppressants are known to effectively control ulcerative colitis (UC), some post-OLT patients develop exacerbation of preexisting UC or de novo UC. Although aminosalicylates and corticosteroid courses are usually effective to treat such UC, several patients have developed uncontrollable disease and required colectomies. CASE REPORT: We have reported a patient who developed de novo UC after OLT to treat liver cirrhosis and hepatocellular carcinoma associated with hepatitis B virus (HBV) infection. Existence of the HBV infection made us avoid to increase the corticosteroid dose or to use other immunosuppressants such as azathioprine or infliximab. CONCLUSIONS: In this patient, granulocyte and monocyte apheresis was highly effective in terms of inducing remission of de novo UC. No adverse event was noted.

Multiple cytokine-producing testicular malignant lymphoma with clinical symptoms resembling infectious signs.

We present the case of a 64-year-old male with painful swelling of the bilateral testes and epididymides, high fever, leukocytosis, and an elevated C-reactive protein (CRP) level. This is the first case report of testicular diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) immunostained for multiple cytokines and their receptors, which clearly demonstrates that tumor cells express multiple cytokines [interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF)] and their receptors [IL-6 receptor (IL-6R) and G-CSF receptor (G-CSFR)]. The clinical course showed that the reduction in tumor size was accompanied by a corresponding improvement in clinical symptoms and peripheral blood findings. Such clinical investigation may lead clinicians to misdiagnose inflammatory disease rather than neoplastic disease. Recognizing this paraneoplastic phenomenon associated with some cases of testicular DLBCL, NOS is important. In addition, this case suggests that the growth of tumor cells may be promoted through autocrine mechanisms of IL-6 and G-CSF, which are produced by tumor cells. The possibility that these cytokines can be produced by tumor cells and can accelerate tumor proliferation should be considered to be a cause of severe clinical symptoms, an aggressive clinical course, and an indication of the necessity of treatment. Certain cytokines may be used as tumor markers in some cases of DLBCL, NOS.

The expression of PTEN in the development of mouse cochlear lateral wall.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that regulates various cell processes including proliferation, growth, synaptogenesis, neural and glioma stem/progenitor cell renewal. In addition, PTEN can regulate sensory cell proliferation and differentiation of hair bundles in the mammalian cochlea. In this study we use immunofluorescence, Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) to reveal the expression of PTEN in the developing cochlear lateral wall, which is crucial for regulating K(+) homeostasis. Relatively high levels of PTEN are initially expressed in the marginal cells (MCs) of the lateral wall at embryonic day (E) 17.5 when they start to differentiate. Similarly high levels are subsequently expressed in differentiating root cells (RCs) at postnatal day (P) 3 and then in spiral ligament fibrocytes (SLFs) at P 10. In the mature cochlea, PTEN expression is low or undetectable in MCs and SLFs but it remains high in RCs and their processes. The expression pattern for PTEN in the developing lateral wall suggests that it plays a critical role in the differentiation of the cellular pathways that regulate K(+) homeostasis in the cochlea.

Association between underweight and taste sensitivity in middle- to old-aged nursing home residents in Sri Lanka: a cross-sectional study.

Low taste sensitivity may be one factor related to undernutrition, which is a major problem in developing countries. The purpose of this cross-sectional study was to examine the association between underweight, one indicator of undernutrition, and taste sensitivity in middle- to old-aged Sri Lankan nursing home residents. Participants were 946 residents with BMI of <25·0 from 25 nursing homes. Data were obtained on height, weight, taste sensitivity, subjective taste ability, sex, age, ethnicity, number of years in nursing homes, activities of daily living (ADL), frequency of exercise, bowel movements, smoking status, drinking status, current number of chronic diseases, number and kinds of medications used, self-reporting questionnaire 20 (SRQ20), subjective smell ability, number of teeth present, Eichner index and flow rate of saliva. Low sensitivity to bitter taste, being male, old age, low ADL, smoking experience, drinking experience, fewer medications used and no use of medication for hypertension and diabetes were each associated with underweight (P < 0·05). In a multilevel Poisson regression model adjusted for sex, age, ADL, smoking status, drinking status, number of medications used, use of medication for hypertension and diabetes and flow rate of saliva, subjects with low sensitivity (>0·003% quinine hydrochloride dihydrate) to bitter taste had a significant 1·70 times higher prevalence ratio (95% confident interval 1·04-2·80) for underweight compared with those with high sensitivity (0·0001% quinine hydrochloride dihydrate). These results suggest that low taste sensitivity to bitter taste may be one factor related to underweight.

An approach for plasma cell myeloma diagnosis by two-color flow cytometry based on kappa/lambda ratios of CD38-gated plasma cells.

Criteria from the World Health Organization (WHO) are commonly used to diagnose plasma cell myeloma (PCM), but they are complex and require several laboratory parameters. To differentiate reactive plasmacytosis from clonal plasma cell neoplasms, such as PCM, it is important to accurately determine the expression of the cytoplasmic immunoglobulin (cIg) light chain (LC). Through retrospective analyses, we selected the patients with PCM, and analyzed records of 52 PCM patients, who underwent bone biopsies, and final diagnosis of PCM was established according to WHO criteria, and 22 controls. In the present study, all samples were analyzed by flow cytometry (FC) in the side scatter vs CD38 histogram mode, and the CD38-gated plasma cell population was identified. The positive cell ratios of kappa and lambda to plasma cell populations were analyzed. PCM cells were distinguished from normal plasma cells by a cut-off level between 0.80 and 3.3, a sensitivity of 90.3 percent, and a specificity of 81.1 percent. Two-color FC analysis is simple to perform, inexpensive, and clinically relevant data are obtained soon after completion of the FC measurements. It could be one of the helpful tools in the diagnosis of PCM. The correct diagnosis of PCM can be achieved more simply, efficiently, and rapidly by combining this method.

Promotion of DNA repair by nuclear IKKß phosphorylation of ATM in response to genotoxic stimuli.

Ataxia-telangiectasia mutated (ATM) is one of the key molecules involved in the cellular response to DNA damage. A portion of activated ATM is exported from the nucleus into the cytoplasm, where it activates the I kappa B kinase/nuclear factor kappa B (IKK/NF-κB) signaling pathway. It has been thought that activated IKKß, which is a critical kinase for NF-κB activation, generally resides in the cytoplasm and phosphorylates cytoplasmic downstream molecules, such as IκBα. Here, we identified a new role for IKKß during the response to DNA damage. ATM phosphorylation in response to alkylating agents consisted of two phases: the early phase (up to 3 h) and late phase (after 6 h). A portion of the activated IKKß generated during the DNA damage response was found to translocate into the nucleus and directly phosphorylate ATM in the late phase. Furthermore, the phosphorylation of ATM by nuclear IKKß was suggested to promote DNA repair. In parallel, activated IKKß induced classical NF-κB activation and was involved in anti-apoptosis. Our findings define the function of IKKß during the response to DNA damage, which promotes cell survival and DNA repair, and maintains cellular homeostasis.

Co-expression of multiple cytokines and their receptors in primary clear cell sarcoma of the pubic bone with features of a small round cell tumor.

We present the case of an 81-year-old man with primary clear cell sarcoma (CCS) of the pubic bone with an associated aggressive clinical course. The patient's laboratory tests showed marked leukocytosis, elevated levels of C-reactive protein and multiple cytokines, including interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF). Histological examination showed monomorphic small cells predominantly arranged as a diffuse sheet with morphological features of a small round cell tumor (SRCT). Immunohistochemical staining indicated that the tumor cells were positive for HMB45, S100, Melan A, IL-6, IL-6 receptor, G-CSF, and G-CSF receptor and negative for cytokeratin (AE1/AE3) and epithelial membrane antigen. To the best of our knowledge, this is the first case report of aggressive primary CCS of the pubic bone with features of SRCT showing the production and co-expression of multiple cytokines and their receptors. Thus, we suggest that proliferation through an IL-6- and G-CSF-associated autocrine mechanism may play an important role in the aggressive clinical course and poor prognosis of some CCSs showing features of SRCT.

Effects of subchronic inhalation exposure to ethyl tertiary butyl ether on splenocytes in mice.

Ethyl tertiary-butyl ether (ETBE) is a motor fuel oxygenate used in reformulated gasoline. The current use of ETBE in gasoline or petrol is modest but increasing. To investigate the effects of ETBE on splenocytes, mice were exposed to 0 (control), 500 ppm, 1750 ppm, or 5000 ppm of ETBE by inhalation for 6 h/day for 5 days/wk over a 6- or 13-week period. Splenocytes were harvested from the control and exposed mice, and the following cell phenotypes were quantified by flow cytometry: (1) B cells (PerCP-Cy5.5-CD45R/B220), (2) T cells (PerCP-Cy5-CD3e), (3) T cell subsets (FITC-CD4 and PE-CD8a), (4) natural killer (NK) cells (PE-NK1.1), and (5) macrophages (FITC-CD11b). Body weight and the weight of the spleen were also examined. ETBE-exposure did not affect the weight of the spleen or body weight, while it transiently increased the number of RBC and the Hb concentration. The numbers of splenic CD3+, CD4+, and CD8+ T cells, the percentage of CD4+ T cells and the CD4+/CD8+ T cell ratio in the ETBE-exposed groups were significantly decreased in a dose-dependent manner. However, ETBE exposure did not affect the numbers of splenic NK cells, B cells, or macrophages or the total number of splenocytes. The above findings indicate that ETBE selectively affects the number of splenic T cells in mice.