Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress.

Background: Oxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). This study investigated the association between genetic variations in antioxidant enzymes and the efficacy of ADT as well as its biological background. Patients and methods: The non-synonymous or promoter-locating polymorphisms of antioxidant enzymes were examined as well as the time to CRPC progression and overall survival in 104 and 92 patients treated with ADT for metastatic and non-metastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide-resistant cells. Results: In metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 and CT/TT allele in CAT rs564250 were associated with a significantly lower risk of progression to CRPC and all-cause death compared with homozygotes of the major AA allele (hazard ratio [HR]; [95% confidence interval (CI)], 0.55 [0.34-0.86], P = 0.0086) and CC allele (HR; [95% CI], 0.48 [0.24-0.88], P = 0.016), respectively. On multivariate analyses, only GSTM3 rs7483 was associated with significant progression risk (AG/GG versus AA; HR; [95% CI], 0.45 [0.25-0.79], P = 0.0047) even after Bonferroni adjustment. In non-metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 was associated with a significantly lower risk of progression to CRPC (HR; [95% CI], 0.35 [0.10-0.93], P = 0.034) and all-cause death (HR; [95% CI], 0.26 [0.041-0.96], P = 0.043) compared with the AA allele. Intracellular reactive oxygen species levels were increased, accompanied with augmented GSTM3 expression in both castration-resistant and enzalutamide-resistant cells. Conclusions: Differential activity of antioxidant enzymes caused by the polymorphism in GSTM3 may contribute to resistance to hormonal therapy through oxidative stress. The GSTM3 rs7483 polymorphism may be a promising biomarker for prostate cancer patients treated with ADT.

The prognostic impact of serum testosterone during androgen-deprivation therapy in patients with metastatic prostate cancer and the SRD5A2 polymorphism.

BACKGROUND: Although testosterone suppression during androgen-deprivation therapy (ADT) and obesity have been reported to affect ADT efficacy, there are few comprehensive analyses on the impact on ADT outcome. Recently, we demonstrated that the SRD5A2 polymorphism was associated with metastatic prostate cancer prognosis. Therefore, in this study, we investigated the relationship between ADT serum testosterone levels or body mass index (BMI) and the prognosis among men treated with primary ADT for metastatic prostate cancer. In addition, we examined the association of serum testosterone levels during ADT with the SRD5A2 polymorphism. METHODS: This study included 96 Japanese patients with metastatic prostate cancer. The relationship between clinicopathological parameters, including serum testosterone levels during ADT and BMI, and progression-free survival, overall survival and survival from progression following primary ADT treatment for metastatic prostate cancer was examined. Additionally, the association between the SRD5A2 gene polymorphism (rs523349) and serum testosterone levels during ADT was examined in 86 cases. RESULTS: Among clinicopathological parameters, the lowest quartile of serum testosterone levels during ADT was a significant predictor of better overall survival as well as survival from castration resistance. However, BMI was not associated with prognosis. The CC allele in the SRD5A2 gene (rs523349), encoding the less active 5α-reductase, was associated with lower serum testosterone levels during ADT. CONCLUSIONS: Taken together, these findings revealed a dramatic suppression of serum testosterone by ADT was associated with better survival among men with metastatic prostate cancer that have undergone primary ADT, which may be affected by the SRD5A2 gene polymorphism.

EP2 signaling mediates suppressive effects of celecoxib on androgen receptor expression and cell proliferation in prostate cancer.

BACKGROUND: Non-steroidal anti-inflammatory drugs inhibit the activity of cyclooxygenases (COXs), and their usage reduces the risks associated with prostate cancer. Celecoxib is a selective COX-2 inhibitor and reported to prevent the progression of prostate cancer. However, the mechanisms involved remain unclear. In this study, we investigated the suppression of prostate cancer growth by celecoxib and elucidated the biological relevance of the inhibited pathway in prostate cancer cell lines. METHODS: Western blotting, quantitative real-time PCR and cell proliferation assay were used to resolve the mechanism of celecoxib in prostate cancer cell line PC3, LNCaP and their derivatives. RESULTS: Celecoxib induced apoptosis and downregulated EP2, CREB and androgen receptor (AR). Moreover, EP2 antagonist downregulated CREB as well as COX-2 and AR, resulting in the suppression of cell proliferation. Furthermore, EP2 and CREB knockdown induced AR downregulation, indicating that AR suppression by celecoxib is mediated by EP2/CREB signaling. CONCLUSIONS: Celecoxib exerts antitumor activity through EP2 signaling regulating AR and COX-2 expression. Furthermore, in addition to celecoxib, therapeutics targeting EP2 may also be promising against prostate cancers.

Polymorphisms of the androgen transporting gene SLCO2B1 may influence the castration resistance of prostate cancer and the racial differences in response to androgen deprivation.

BACKGROUND: Organic anion-transporting polypeptides (OATPs) encoded by SLCO mediate the cellular uptake of many compounds, including androgens. SLCO1B3 and SLCO2B1 are polymorphic, and single-nucleotide polymorphisms of those genes alter androgen transport efficiency. We aimed to investigate the association between genetic variations in SLCOs and the progression to castration-resistant prostate cancer (CRPC). METHODS: We studied the progression to CRPC for the SLCO1B3 rs4149117 and SLCO2B1 rs12422149 genotypes in 87 prostate cancer patients who received androgen deprivation therapy (ADT). Data were analyzed using the χ(2) test, Kaplan-Meier survival analysis and Cox proportional hazard model. RESULTS: SLCO3B1 genotypes were not significantly associated with the time to progression (TTP); however, patients carrying the active androgen transport SLCO2B1 genotype (GG allele) exhibited a median TTP that was 7 months shorter than that of patients with impaired androgen-transporting activity SLCO2B1 polymorphisms (GA/AA alleles) (10.0 vs 17.0 months, P=0.004). Active androgen transport genotypes of SLCO2B1 (GG allele) occurred more frequently in African and Caucasian populations than in Japanese and Han Chinese populations (P<0.001). CONCLUSIONS: These data suggest that SLCO2B1 rs12422149 variants could provide prognostic value for prostate cancer patients treated with ADT and influence ethnic differences in response to ADT. Active androgen import may be one of the underlying mechanisms of resistance to ADT, and androgen-transporting systems could provide novel biomarkers and targets for CRPC treatment.

Short-term outcomes of local correction of stoma prolapse with a stapler device.

BACKGROUND: The aim of the present study was to classify the short-term outcomes of local correction of stoma prolapse with a stapler device. METHODS: The medical records of 11 patients undergoing local correction of stoma prolapse using a stapler device were retrospectively reviewed. RESULTS: No mortality or morbidity was observed after the surgery. Median operative time was 35 min (range 15-75 min), and blood loss was minimal. Median duration of follow-up was 12 months (range 6-55 months). One of the 11 patients had a recurrent stoma prolapse. CONCLUSIONS: This technique can be a feasible, safe and minimally invasive correction procedure for stoma prolapse.

Incidence of complications in patients with benign gynecological diseases by BMI and level of complexity of laparoscopic surgery.

INTRODUCTION: Laparoscopic surgery has become a standard surgical method for benign gynecological diseases, but the technique can still be accompanied, albeit infrequently, by intraoperative or postoperative complications. It has been postulated that the frequency of complications differs according to patient body habitus or surgical challenge level. We evaluated the relationship between the complication rate at different levels of surgery and BMI in patients with benign gynecological diseases who have undergone laparoscopic surgery at our hospital. METHODS: A total of 3231 patients who underwent laparoscopic surgery between 1989 and 2010 were enrolled in this study retrospectively. They were classified into four groups by surgery level (diagnostic laparoscopy or minor, major, or advanced laparoscopic surgery). At each challenge level, patients were classified into three groups based on BMI (as defined by the WHO): A group (underweight), BMI < 18.5; B group (healthy), BMI ≥ 18.5 and < 25; and C group (overweight), BMI ≥ 25. We compared the complication rates between the groups at each level of surgical challenge. RESULTS: There was no difference in the complication rate between groups A, B and C at any of the surgical challenge levels. However, at the higher surgical difficulty levels, a higher incidence of overall complications was observed. CONCLUSION: The complication rate differs between surgical levels, and complications can occur in any type of surgery, irrespective of the body habitus of the patient. The complication rate is higher when difficult surgical methods are employed, and extra caution is needed.

Estimation of preoperative uterine weight in uterine myoma and uterine adenomyosis.

INTRODUCTION: Uterine myoma and uterine adenomyosis frequently occur in sexually mature women. Total hysterectomy is the treatment of choice when the symptoms are severe. To select an operative procedure from abdominal, vaginal, and laparoscopic methods, precise estimation of the preoperative uterine weight is desired. In this study, we estimated the preoperative uterine weight with preoperative images in cases of uterine myoma and uterine adenomyosis. METHODS: We evaluated 403 patients with uterine myoma or uterine adenomyosis (uterus < 1000 g) between 1996 and 2010. All patients underwent a preoperative MRI and received a hysterectomy with the uterine weight recorded. Based on MR images, we measured (in centimeters) the maximum longitudinal diameter in the sagittal section (a), the maximum lateral diameter (b) and the maximum longitudinal diameter in the transverse section (c) of each uterus. A correlation coefficient was calculated between the weight of the removed uterus and the value of a × b × c for each individual uterus. Also, a regression analysis was performed between x (the value of a × b × c) and y (weight of the removed uterus). RESULTS: A strong correlation was shown between the weight of the removed uterus and the value of a × b × c (r = 0.81, P < 0.01). As a result of the regression analysis, the regression equation y = 0.35x + 107 (R(2) = 0.66, P < 0.01) was obtained. CONCLUSION: In this study, the estimated weight of the uterus was calculated by the formula y = 0.35x + 107 (x = a × b × c), and this could be the determining factor in choosing a surgical method for hysterectomy.

Influence of menopause on mandibular bone quantity and quality in Japanese women receiving dental implants.

SUMMARY: The purpose of this study was to evaluate the effect of menopause on bone mineral density and bone width of the mandible. Results indicate that menopause affects the bone quality and quantity of the partially edentulous molar region of the mandible, which should be considered in dental implant treatment for postmenopausal women. INTRODUCTION: The recovery of oral function with dental implant is clinically effective and highly predictable. Bone quantity and quality at the implant installation site affect its prognosis; however, the effects of menopause on jaw bone have not been well documented. The purpose of this study was to evaluate the effect of menopause on bone mineral density (BMD) and bone width of the mandible. METHODS: The subjects were 72 female patients with a partially edentulous molar region of the mandible: 30 premenopausal and 42 postmenopausal women aged 30 to 70 years. Trabecular BMD was measured with quantitative computed tomography. Trabecular region width (TW) and cortical width (CW) were measured with CT. The BMD, TW, and CW of the two groups were compared. RESULTS: The trabecular BMD of postmenopausal women was lower than that of the premenopausal women. The TW of postmenopausal women was greater than that of premenopausal women, whereas the CW of postmenopausal women was significantly smaller than that of premenopausal women. In all these women, BMD correlated negatively with TW and positively with CW. In the premenopausal women, BMD negatively correlated with TW, but it did not correlate with CW. In the postmenopausal women, there was no correlation between BMD and bone width. CONCLUSION: These results indicate that menopause affects the bone quality and quantity of the partially edentulous molar region of the mandible, which should be considered in dental implant treatment for postmenopausal women.

Total abdominal hysterectomy versus laparoscopically-assisted vaginal hysterectomy versus total vaginal hysterectomy.

INTRODUCTION: While total abdominal hysterectomy (TAH) and total vaginal hysterectomy (TVH) are conventional procedures, we have actively introduced laparoscopically-assisted vaginal hysterectomy (LAVH) since its advent. This study was the first attempt to retrospectively compare the surgical results, including invasiveness, among the three methods of performing a hysterectomy. METHODS: The subjects included 1181 patients who underwent total hysterectomies (TAH, n=465; LAVH, n=629; TVH, n=87) due to uterine fibroids or uterine adenomyosis at our hospital between January 1995 and December 2009. The mean age, parity, weight of the removed uterus, operative time, blood loss, rates of intra- and post-operative complications, length of post-operative hospital stay, leukocyte count, and CRP and hemoglobin levels were compared. RESULTS: The operative time was significantly longer in the LAVH group than the other two groups. Blood loss was significantly greater in the TAH group than the LAVH and TVA groups. The rates of intra- and post-operative complications were significantly higher in the TAH group than the LAVH group. The CRP level and leukocyte count were significantly lower in the LAVH group than the TAH and TVH groups. CONCLUSION: LAVH can be applied to nulligravidas or patients with relatively large uteri and it is proved less invasive than TAH and TVH in this study. We recommend active application of LAVH.

Human heterochromatin protein 1 isoform HP1beta enhances androgen receptor activity and is implicated in prostate cancer growth.

There are currently few successful therapies for castration-resistant prostate cancer (CRPC). CRPC is thought to result from augmented activation of the androgen/androgen receptor (AR) signaling pathway, which could be enhanced by AR cofactors. In this study, heterochromatin protein 1beta (HP1beta), but not HP1alpha or HP1gamma was found to be an AR cofactor. HP1beta interacted with the AR, and enhanced the DNA-binding ability of AR to androgen-responsive element in the prostate-specific antigen enhancer and promoter regions, and to increase the transcription of AR target genes. In prostate cancer (PCa) tissues, HP1beta expressions correlated with Gleason score and tri-methylation levels of histone H3 lysine 9. Silencing of HP1beta suppressed the growth of AR-expressing PCa cells by inducing cell-cycle arrest at the G(1) phase, similar to inhibition of androgen/AR signaling. Furthermore, HP1beta was overexpressed in castration-resistant LNCaP derivative CxR cells, and HP1beta knockdown also suppressed the cell growth in CxR cells. These findings indicate that HP1beta is involved in the proliferation of AR-expressing PCa cells and progression to CRPC as an AR coactivator. Modulation of HP1beta expression or function might be a useful strategy for developing novel therapeutics for PCa, even in CRPC.

Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression.

There are few successful therapies for castration-resistant prostate cancer (CRPC). Recently, CRPC has been thought to result from augmented androgen/androgen receptor (AR) signaling pathway, for most of which AR overexpression has been observed. In this study, Twist1, a member of basic helix-loop-helix transcription factors as well as AR was upregulated in response to hydrogen peroxide, and the response to which was abolished by an addition of N-acetyl-L-cysteine and Twist1 knockdown. In addition, castration-resistant LNCaP derivatives and hydrogen peroxide-resistant LNCaP derivatives exhibited a similar phenotype to each other. Then, both castration and AR knockdown increased intracellular reactive oxygen species level. Moreover, Twist1 was shown to regulate AR expression through binding to E-boxes in AR promoter region. Silencing of Twist1 suppressed cell growth of AR-expressing LNCaP cells as well as castration-resistant LNCaP derivatives by inducing cell-cycle arrest at G1 phase and cellular apoptosis. These findings indicated that castration-induced oxidative stress may promote AR overexpression through Twist1 overexpression, which could result in a gain of castration resistance. Modulation of castration-induced oxidative stress or Twist1/AR signaling might be a useful strategy for developing a novel therapeutics in prostate cancer, even in CRPC, which remains dependent on AR signaling by overexpressing AR.

Twist and p53 reciprocally regulate target genes via direct interaction.

Twist is basic helix-loop-helix transcription factor that binds to E-boxes in gene promoters. Twist possesses an oncogenic function by interfering with the tumor suppressor function of p53. Using a membrane pull-down assay, we found that Twist directly interacts with p53 and that this interaction underlies the inhibitory effects on p53 target gene expression. Twist interacted with the DNA-binding domain of p53 and suppressed the DNA-binding activity of p53. Transcriptional activation of the p21 promoter by p53 was significantly repressed by the expression of Twist. On the other hand, p53 interacted with the N-terminal domain of Twist and repressed Twist-dependent YB-1 promoter activity. Importantly, we found that p53-dependent growth suppression was canceled by the expression of either Twist or YB-1. Thus, our data suggest that Twist inhibits p53 function via a direct interaction with p53.

Interleukin-10 gene transfer to peritoneal mesothelial cells suppresses peritoneal dissemination of gastric cancer cells due to a persistently high concentration in the peritoneal cavity.

Interleukin (IL)-10 has potent biological properties including an inhibitory action on the proliferation and metastasis of various cancer cells. However, it is difficult to maintain a high concentration of this cytokine as it has a short half life. In this study, we evaluated whether peritoneal mesothelial cells (PMCs) could be suitable for maintaining a high concentration of IL-10 using adenoviral gene transfer. We also evaluated the therapeutic effects of an intraperitoneal injection with adenoviral vector containing mouse IL-10 gene (Ad-mIL-10) using a mouse peritoneal dissemination model of MKN45 gastric cancer cells. We demonstrated that in vitro transfection efficiency of a recombinant adenovirus containing the bacterial beta-galactosidase gene (Ad-LacZ) was approximately 10-fold higher for primarily isolated PMCs than MKN45. The entire peritoneum was transfected until 3 weeks after an intraperitoneal Ad-LacZ injection. Ad-mIL-10 treatment increased intraperitoneal IL-10 levels until 3 weeks after treatment, and then significantly inhibited peritoneal cancer growth by inhibiting angiogenesis. This treatment also improved cachexia and prolonged mice survival. We thus concluded that IL-10 gene transfer in PMCs could be a new strategy for the prevention of peritoneal dissemination of gastric cancer due to the resulting persistently high IL-10 concentration in the peritoneal cavity.

Transient antiphospholipid antibodies associated with acute infections in children: a report of three cases and a review of the literature.

We describe two previously healthy children who had multiple ecchymoses several days after acute infection. In both cases, the prothrombin time (PT) and the activated partial thromboplastin time (APTT) were prolonged. Further examinations revealed the presence of lupus anticoagulant (LA), phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT), and low serum complement. In both cases, we confirmed the presence of a serum immune complex. The patients' symptoms improved spontaneously within 1 week, and all laboratory data normalized within several months. We also describe another asymptomatic case positive for LA and aPS/PT presumably associated with cytomegalovirus infection. The prevalence of transient antiphospholipid antibodies associated with viral infections in children must be much higher than we expected. We have to take it into consideration when we see abnormal coagulation results, but the occurrence of significant bleeding symptoms is rare.

Late-onset neuropsychological symptoms in a Japanese patient with megalencephalic leukoencephalopathy with subcortical cysts.

We herein report a Japanese patient with megalencephalic leukoencephalopathy with subcortical cysts (MLC) who developed late-onset neuropsychological symptoms. He demonstrated characteristic clinical features of MLC during childhood, such as slowly progressive megalencepaly, motor impairment with ataxia and spasticity, mild mental retardation, and well-controlled epilepsy. Thereafter, he showed specific neuropsychological symptoms, such as motor and vocal tics, compulsive behavior, perseveration, acquired stuttering, and dystonia since the age of 12. His performance abilities had been unchanged but his verbal abilities had degraded during the past 14 years. Higher cortical dysfunction tests revealed a frontal lobe dysfunction. On repeated brain MRI, a leukoencephalopathy with subcortical cysts remained stationary from infancy. On single photon emission computed tomography (SPECT), a hypoperfusion in the frontal lobe was detected at the age of 3.5 and 17, but the severity of hypoperfusion was also unchanged, respectively. Our results indicate that the frontal lobe dysfunction may be relevant to the late-onset neuropsychological symptoms with MLC.

Colon stenosis caused by old portal vein thrombosis.

A 58-year-old female with a history of portal vein thrombosis was referred to our hospital with abdominal pain and distention. Colon fiber and enema of the colon showed stenosis at the transverse colon and the ascending colon, with edematous mucosa. Laparotomy revealed no abnormal findings other than chronic ischemia of the colon. To our knowledge, this is the first reported case of colon stenosis caused by portal vein thrombosis.

Large cholesterol polyp of the gallbladder mimicking gallbladder carcinoma.

Gallbladder tumors larger than 10 mm in diameter have a high incidence of malignancy. We report an extremely rare case of a large cholesterol polyp of the gallbladder mimicking gallbladder carcinoma. Ultrasonography and computed tomography showed a larger papillary mass in the fundus of the gallbladder with a maximum diameter of about 30 mm, the largest gallbladder polyp ever reported to our knowledge.