Body size throughout the life-course and incident benign prostatic hyperplasia-related outcomes and nocturia.

BACKGROUND: Existing evidence suggests that there is an association between body size and prevalent Benign Prostatic Hyperplasia (BPH)-related outcomes and nocturia. However, there is limited evidence on the association between body size throughout the life-course and incident BPH-related outcomes. METHODS: Our study population consisted of men without histories of prostate cancer, BPH-related outcomes, or nocturia in the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (n = 4710). Associations for body size in early- (age 20), mid- (age 50) and late-life (age ≥ 55, mean age 60.7 years) and weight change with incident BPH-related outcomes (including self-reported nocturia and physician diagnosis of BPH, digital rectal examination-estimated prostate volume ≥ 30 cc, and prostate-specific antigen [PSA] concentration > 1.4 ng/mL) were examined using Poisson regression with robust variance estimation. RESULTS: Men who were obese in late-life were 25% more likely to report nocturia (Relative Risk (RR): 1.25, 95% Confidence Interval (CI): 1.11-1.40; p-trendfor continuous BMI < 0.0001) and men who were either overweight or obese in late-life were more likely to report a prostate volume ≥ 30 cc (RRoverweight: 1.13, 95% CI 1.07-1.21; RRobese: 1.10, 95% CI 1.02-1.19; p-trendfor continuous BMI = 0.017) as compared to normal weight men. Obesity at ages 20 and 50 was similarly associated with both nocturia and prostate volume ≥ 30 cc. Considering trajectories of body size, men who were normal weight at age 20 and became overweight or obese by later-life had increased risks of nocturia (RRnormal to overweight: 1.09, 95% CI 0.98-1.22; RRnormal to obese: 1.28, 95% CI 1.10-1.47) and a prostate volume ≥ 30 cc (RRnormal to overweight: 1.12, 95% CI 1.05-1.20). Too few men were obese early in life to examine the independent effect of early-life body size. Later-life body size modified the association between physical activity and nocturia. CONCLUSIONS: We found that later-life body size, independent of early-life body size, was associated with adverse BPH outcomes, suggesting that interventions to reduce body size even late in life can potentially reduce the burden of BPH-related outcomes and nocturia.

Multi-institutional Outcomes and Associations After Excision and Primary Anastomosis for Radiotherapy-associated Bulbomembranous Urethral Stenoses Following Prostate Cancer Treatment.

OBJECTIVE: To evaluate the outcomes of excision and primary anastomosis (EPA) for radiation-associated bulbomembranous stenoses using a multi-institutional analysis. The treatment of radiation-associated urethral stenosis is typically complex owing to the adverse impact of radiation on adjacent tissue. METHODS: An IRB-approved multi-institutional retrospective review was performed on patients who underwent EPA for bulbomembranous urethral stenosis following prostate radiotherapy. Preoperative patient demographics, operative technique, and postoperative outcomes were abstracted from 1/2007-6/2018. Success was defined as voiding per urethra without the need for endoscopic treatment and a minimum follow-up of 12 months. RESULTS: One hundred and thirty-seven patients from 10 centers met study criteria with a mean age of 69.3 years (50-86), stenosis length of 2.3 cm (1-5) and an 86.9% (119/137) success rate at a mean follow-up 32.3 months (12-118). Univariate Cox regression analysis identified increasing patient age (P = .02), stricture length (P <.0001) and combined modality radiotherapy (P = .004) as factors associated with stricture recurrence while body mass index (P = .79), diabetes (P = .93), smoking (P = .62), failed endoscopic treatment (P = .08) and gracilis muscle use (P = .25) were not. On multivariate analysis, increasing patient age (H.R.1.09, 95%CI 1.01-1.16; P = .02) and stenosis length (H.R.2.62, 95%CI 1.49-4.60; P = .001) remained associated with recurrence. Subsequent artificial urinary sphincter was performed in 30 men (21.9%), of which 25 required a transcorporal cuff and 5 developed cuff erosion. CONCLUSIONS: EPA for radiation-associated urethral stenosis effectively provides unobstructed instrumentation-free voiding. However, increasing stenosis length and age are independently associated with surgical failure. Patients should be counseled that further surgery for incontinence may be necessary.

Long-term follow-up of urethral reconstruction for blunt urethral injury at a young age: urinary and sexual quality of life outcomes.

INTRODUCTION: Little is known about long-term patient-reported outcomes following surgical repair for pediatric blunt urethral trauma. OBJECTIVE: The purpose was to evaluate long-term urinary outcomes, sexual function, and quality of life (QOL) of patients who undergo urethroplasty for blunt urethral trauma in childhood. STUDY DESIGN: After IRB approval, we retrospectively reviewed the records of patients who sustained blunt urethral injury at ≤18 years and underwent urethroplasty at our institution between 1978 and 2013. We then used a web-based survey to assess urinary/sexual/ejaculatory function and overall QOL using validated questionnaires. RESULTS: Of 68 eligible patients, 15 were able to be contacted (table). Median age of injury, age at urethroplasty, and age at follow-up were 17 (4-18), 17 (5-20), and 19 (13.5-21.5) years, respectively. The stricture was membranoprostatic in eight and bulbar in seven patients, with median length of 2 (1.6-2.6) cm. Excision/primary anastomosis was performed in all but three patients who required a buccal graft. Overall, 80% were 'very satisfied' and 20% were 'satisfied' with surgery. One patient reported a subsequent urethral intervention. On urethral stricture surgery patient-reported outcome measurement, the median bother (0 least, 24 worst) was 10 (8-12.5). The force of urine stream (1 strongest, 4 weakest) was 2 (1.5-2), with no report of urinary incontinence. The median Sexual Health Inventory for Men score (0 worst, 25 perfect) was 24 (22.5-24). The median ejaculatory function score (0 worst, 15 normal) was 14 (13-14.75). Six patients had fathered children and none reported infertility. Three patients reported <30° penile curvature not interfering with sex. Median QOL (0 worse, 10 best) was 8 (7.5-8). CONCLUSIONS: Urethroplasty after blunt urethral injury in young adult population is associated with a high long-term success rate with a low rate of long-term urinary and sexual consequences in adulthood.

Pelvic lymphadenectomy in prostate cancer.

This review analyzes the anatomy of the prostate gland's lymphatic drainage, the optimal anatomic extend of pelvic lymph node dissection (PLND) and which dissection may be superior, who should undergo a PLND during prostatectomy, and its potential therapeutic benefits and complications. The prostate gland's lymphatic drainage can be variable, but frequently metastatic disease is found in the internal iliac chain. We conclude that the extended PLND yields the most lymph nodes and therefore may be superior. Some have demonstrated an unproven survival benefit after performing an extended PLND, possibly from removal of occult disease or from more accurate staging.

Inhibition of Abl tyrosine kinase enhances nerve growth factor-mediated signaling in Bcr-Abl transformed cells via the alteration of signaling complex and the receptor turnover.

Receptor tyrosine kinase-mediated signaling is tightly regulated by a number of cytoplasmic signaling molecules. In this report, we show that Bcr-Abl transformed chronic myelogenous leukemia (CML) cell lines, K562 and Meg-01, express the receptor for nerve growth factor (NGF), TrkA, on the cell surface; however, the NGF-mediated signal is not particularly strong. Treatment with imatinib, a potent inhibitor of Bcr-Abl tyrosine kinase, downmodulates phosphorylation of downstream molecules. Upon stimulation with NGF, Erk and Akt are phosphorylated to a much greater degree in imatinib-treated cells than in untreated cells. Knockdown of expression of Bcr-Abl using small interfering RNA technique also enhanced NGF-mediated Akt phosphorylation, indicating that Bcr-Abl kinase modifies NGF signaling directly. Imatinib treatment also enhanced NGF signaling in rat adrenal pheochromocytoma cell line PC12 that expresses TrkA and c-Abl, suggesting that it is not only restoration of responsiveness to NGF after blocking oncoprotein activity, but also c-Abl tyrosine kinase per se may be a negative regulator of growth factor signaling. Furthermore, inhibition of Abl tyrosine kinase enhanced clearance of surface TrkA after NGF treatment and simultaneously enhanced NGF-mediated signaling, suggesting that as in neuronal cells 'signaling endosomes' are formed in hematopoietic cells. To examine the role of TrkA in CML cells, we studied cell growth or colony formation in the presence or absence of imatinib with or without NGF. We found that NGF treatment induces cell survival in imatinib-treated CML cell lines, as well as colony formation of primary CD34+ CML cells, strongly suggesting that NGF/TrkA signaling contributes to aberrant signaling in CML.

Fluorescence-based functional assay for Wnt/beta-catenin signaling activity.

Aberrant activation of beta-catenin signaling has been implicated in the development of human cancers. As a Wnt signal transducer, beta-catenin forms a complex with the lymphocyte enhancer-binding factor/T cell factor transcription factor and activates downstream targets that promote cell proliferation. Here we developed a Wnt-dependent beta-catenin-mediated heterologous transactivation system, which consisted of a chimeric transcription factor constructed by fusing the GAL4 DNA-binding domain with the full-length beta-catenin, and a GAL4-responsive reporter expressing GFP. The chimeric transcription factor was highly unstable and exerted no detectable transactivating effect on the GAL4-responsive reporter. However, lithium and Wnt1 significantly stabilized this chimeric transactivator, indicating that this transactivation system is regulated by beta-catenin in a Wnt-responsive fashion. Thus, this transactivation system could be used as a functional reporter to identify potential upstream factors that deregulate beta-catenin signaling during tumorigenesis, as well as to screen for potential anti-cancer agents that specifically inhibit beta-catenin signaling in human tumors.

Tetracycline-regulated gene expression mediated by a novel chimeric repressor that recruits histone deacetylases in mammalian cells.

Regulated gene expression will provide important platforms from which gene functions can be investigated and safer means of gene therapy may be developed. Histone deacetylases have recently been shown to play an important role in regulating gene expression. Here we investigated whether a more tightly controlled expression could be achieved by using a novel chimeric repressor that recruits histone deacetylases to a tetracycline-responsive promoter. This chimeric repressor was engineered by fusing the tetracycline repressor (TetR) with an mSin3-interacting domain of human Mad1 and was shown to bind the tetO(2) element with high affinity, and its binding was efficiently abrogated by doxycycline. The chimeric repressor was shown to directly interact with mSin3 of the histone deacetylase complex. This inducible system was further simplified by using a single vector that contained both a chimeric repressor expression cassette and a tetracycline-responsive promoter. When transiently introduced into mammalian cells, the chimeric repressor system exhibited a significantly lower basal level of luciferase activity (up to 25-fold) than that of the TetR control. When stably transfected into HEK 293 cells, the chimeric repressor system was shown to exert a tight control of green fluorescent protein expression in a doxycycline dose- and time-dependent fashion. Therefore, this novel chimeric repressor provides an effective means for more tightly regulated gene expression, and the simplified inducible system may be used for a broad range of basic and clinical studies.

Peroxisome proliferator-activated receptors: roles in tumorigenesis and chemoprevention in human cancer.

Peroxisome proliferator-activated receptors are nuclear receptors that were isolated for their ability to modulate lipid metabolism. Similar to other members of the nuclear receptor family, peroxisome proliferator-activated receptors bind ligand as heterodimers and exert their effects via transcriptional regulation through their DNA binding domains. During the past decade, it has become clear that peroxisome proliferator-activated receptors also contribute to a variety of different biologic processes, including atherosclerosis, insulin resistance, and more recently, cancer. In this review, we discuss the evidence for the different peroxisome proliferator-activated receptors' roles in tumorigenesis and also their potential application for the treatment and prevention of neoplastic diseases.

Adenoviral vector-mediated gene transfer for human gene therapy.

Human gene therapy promises to change the practice of medicine by treating the causes of disease rather than the symptoms. Since the first clinical trial made its debut ten years ago, there are over 400 approved protocols in the United States alone, most of which have failed to show convincing data of clinical efficacy. This setback is largely due to the lack of efficient and adequate gene transfer vehicles. With the recent progress in elucidating the molecular mechanisms of human diseases and the imminent arrival of the post genomic era, there are increasing numbers of therapeutic genes or targets that are available for gene therapy. Therefore, the urgency and need for efficacious gene therapies are greater than ever. Clearly, the current fundamental obstacle is to develop delivery vectors that exhibit high efficacy and specificity of gene transfer. Recombinant adenoviruses have provided a versatile system for gene expression studies and therapeutic applications. Of late, there has been a remarkable increase in adenoviral vector-based clinical trials. Recent endeavors in the development of recombinant adenoviral vectors have focused on modification of virus tropism, accommodation of larger genes, increase in stability and control of transgene expression, and down-modulation of host immune responses. These modifications and continued improvements in adenoviral vectors will provide a great opportunity for human gene therapy to live up to its enormous potential in the second decade.

[Tumoral angiogenesis--hot topic in science again]. / Tumorska angiogeneza--ponovno vruca znanstvena tema.

Angiogenesis is the formation of new capillary blood vessels. It has a very important role not only in physiological conditions but in the process of malignant tumors growth. Weak muscular layer, chaotical branching and irregular shape, are the characteristics of newly formed tumorous vessels. The number and arrangement of blood vessels differ between benign and malignant tumors. Latest data suggesting that drugs inhibiting angiogenesis can stop growth of malignant tumors made the research on tumorous angiogenesis a hot topic recently. Although reliable in differentiating benign from malignant tumors, two-dimensional ultrasound with color and pulsed Doppler, can not make spatial image of vascular architecture. Three-dimensional (3D) ultrasound with color Doppler allows the investigator to have a three-dimensional architectural picture of tumorous vascular network, and according to the findings it is possible to detect malignant tumors even in doubtful cases.

Characteristics of blood flow in cancer of the uterine cervix.

Blood flow characteristics were measured in patients with histologically proved cervical cancer and compared to normal values. Flow parameters were derived by color and pulsed Doppler ultrasound. The results showed a significant difference in the mean values of resistance index and pulsatility index among the diseased patients and healthy controls. However, the method does not have the required sensitivity for screening purposes, so that its value may mainly be in the follow-up of patients treated conservatively with radiation and chemotherapy.

Ultrasonic mammography without specialized equipment. Comparison with clinical examination and x-rays.

Ultrasonic mammography has been compared with clinical examination and X-ray mammography. Results for the years 1977-79 are shown. A general purpose compound scanner and a custom made water delay bath are used. Twenty three percent of patients undergoing breast examination had an ultrasonic scan. The lowest limit for cyst detection in 4 mm diameter and for solid tumours about 10 mm. Comparison of the three methods shows an agreement of approx. 87% in benign lesions (i.e. agreement in the type of benign disease), and between 16/18 and 17/18 in malignant lesions (comparison of suspicion of malignancy only). As a result of these findings ultrasound is used in our department as a useful auxiliary method.

Effects of patient positioning and of thickness variations on radiotherapy.

Correct patient positioning is essential for good aiming in radiotherapy. This can be achieved using back and side pointers, but sometimes these devices are not being used in order to simplify and make the positioning faster. The effects of such a simplification have been studied and measured. The results of this experimental study show that in thicker patients (over 24 cm) the use of back and side pointers is of great importance, because the variation of the patient thickness and angulation can significantly influence the aiming angles and dose percentages.