Comparison of Voiding Dysfunction Phenotypes in Women with Interstitial Cystitis/Bladder Pain and Myofascial Pelvic Pain: Results from the ICEPAC Trial.

OBJECTIVE: To evaluate whether voiding parameters differ in patients with the common overlapping pelvic pain disorders, interstitial cystitis/bladder pain syndrome (IC/BPS), and myofascial pelvic pain (MPP). METHODS: Uroflow and voiding diary assessed voiding phenotypes in this prospective cohort study (ICEPAC) of women comparing IC/BPS, IC/BPS +MPP, MPP, and healthy control (HC) subjects. RESULTS: In 36 HC, 24 IC/BPS, 37 IC/BPS + MPP, and 14 MPP subjects, the voiding diary measurements indicate lower voided volumes in IC/BPS and IC/BPS + MPP groups (185 ± 24 mL, 169 ± 20 mL, respectively) compared to HC and MPP groups (294 ± 24 mL, 226 ± 36 mL, respectively; P <.05, P <.05), as well as higher 24-hour voiding frequency (11.6 ± 0.8 and 11 ± 1.2 voids/24 hours, respectively; HC 7.1 ± 0.5 voids/24 hours; P <.05, P <.05; MPP group 9 ± 1.2 voids/24 hours; P <.05, P <.05). Uroflow showed higher HC average flow rate (12.87 ± 0.92) compared to IC/BPS, IC/BPS+MPP, and MPP (8.31 ± 1.20, 8.02 ± 0.80, 8.17 ± 1.38, respectively; P <.01, P <.01, P <.05) and peak flow rate (27.0 ± 1.83) and IC/BPS, IC/BPS+MPP and MPP (16.20 ± 2.2, 17.33 ± 1.64, 17.21 ± 2.69 respectively; P <.01, P <.01, P <.05). CONCLUSION: This quantitative evaluation of voiding diary and uroflow metrics reveals distinct voiding phenotypes, which can aid in the diagnosis of chronic pelvic pain syndromes. Patients with IC/BPS had more pain with a full bladder despite similar overall pain scores. Peak and average flow rates do not provide any differentiating power between IC/BPS and MPP patients. A longer time to peak flow may favor MPP though this finding needs confirmation.

Metabolic syndrome, inflammation and lower urinary tract symptoms: possible translational links.

BACKGROUND: Epidemiological data suggest that lower urinary tract symptoms (LUTSs) may be associated with metabolic syndrome (MetS). Inflammation has been proposed as a candidate mechanism at the crossroad between these two clinical entities. The aim of this review article is to evaluate the role of MetS-induced inflammation in the pathogenesis and progression of LUTS. METHODS: A systematic review was conducted using the keywords 'metabolic syndrome and lower urinary tract symptoms' within the title search engines including PubMed, Web of Science and the Cochrane Library for relevant research work published between 2000 and January 2015. The obtained literature was reviewed by the primary author (QH) and was assessed for eligibility and standard level of evidence. RESULTS: Total of 52 articles met the eligibility criteria. On the basis of database search during the past 15 years and our systematic review of prospective and retrospective cohorts, case-control trials, observational studies and animal data identified a possible link between MetS-induced inflammation and LUTS including BPH, bladder outlet obstruction, overactive bladder, urinary incontinence and other possible urinary tract abnormalities. CONCLUSIONS: There is convincing evidence to suggest that MetS and inflammation could be important contributors to LUTS in men, particularly in the development of BPH. However, the role of MetS-induced inflammation remains unclear in overactive bladder, urinary incontinence and etiology of LUTS progression.

Combination simvastatin and metformin induces G1-phase cell cycle arrest and Ripk1- and Ripk3-dependent necrosis in C4-2B osseous metastatic castration-resistant prostate cancer cells.

Castration-resistant prostate cancer (CRPC) cells acquire resistance to chemotherapy and apoptosis, in part, due to enhanced aerobic glycolysis and biomass production, known as the Warburg effect. We previously demonstrated that combination simvastatin (SIM) and metformin (MET) ameliorates critical Warburg effect-related metabolic aberrations of C4-2B cells, synergistically and significantly decreases CRPC cell viability and metastatic properties, with minimal effect on normal prostate epithelial cells, and inhibits primary prostate tumor growth, metastasis, and biochemical failure in an orthotopic model of metastatic CRPC, more effectively than docetaxel chemotherapy. Several modes of cell death activated by individual treatment of SIM or MET have been reported; however, the cell death process induced by combination SIM and MET treatment in metastatic CRPC cells remains unknown. This must be determined prior to advancing combination SIM and MET to clinical trial for metastatic CRPC. Treatment of C4-2B cells with combination 4 µM SIM and 2 mM MET (SIM+MET) led to significant G1-phase cell cycle arrest and decrease in the percentage of DNA-replicating cells in the S-phase by 24 h; arrest was sustained throughout the 96-h treatment. SIM+MET treatment led to enhanced autophagic flux in C4-2B cells by 72-96 h, ascertained by increased LC3B-II (further enhanced with lysosomal inhibitor chloroquine) and reduced Sequestosome-1 protein expression, significantly increased percentage of acidic vesicular organelle-positive cells, and increased autophagic structure accumulation assessed by transmission electron microscopy. Chloroquine, however, could not rescue CRPC cell viability, eliminating autophagic cell death; rather, autophagy was upregulated by C4-2B cells in attempt to withstand chemotherapy. Instead, SIM+MET treatment led to Ripk1- and Ripk3-dependent necrosis by 48-96 h, determined by propidium iodide-Annexin V flow cytometry, increase in Ripk1 and Ripk3 protein expression, necrosome formation, HMGB-1 extracellular release, and necrotic induction and viability rescue with necrostatin-1 and Ripk3-targeting siRNA. The necrosis-inducing capacity of SIM+MET may make these drugs a highly-effective treatment for apoptosis- and chemotherapy-resistant metastatic CRPC cells.

Animal models and their use in understanding lower urinary tract dysfunction.

This review will highlight appropriate animal models for the study of a number of disorders involving changes to lower urinary tract function. A major hurdle to the development of animal models for human lower urinary tract disorders is that the clinical pathophysiology of the latter mostly remain idiopathic. Acute injury/inflammation of otherwise healthy animals has often been used to study effects on a target tissue/organ. However, these "acute" models may not adequately address the characteristics of "chronic" visceral disorders. In addition, the relevance of observed changes following acute injury/inflammation, in terms of possible therapeutic targets, may not reflect that which occurs in the human condition. We have therefore emphasized the situations when animal models are required to investigate lower urinary tract disorders and what they should set out to achieve. In particular we have discussed the merits and disadvantages of a number of paradigms that set out to investigate specific lower urinary tract disorders or situations associated with these conditions. These include animal models of overactive bladder, stress urinary incontinence, ageing and congenital defects of the urinary tract and bladder pain syndrome.

Valsalva leak point pressure: steps toward standardization.

Valsalva leak point pressure (VLPP) has been used as the urodynamic indicator of intrinsic sphincteric deficiency in patients with stress urinary incontinence. However, further validation of VLPP as a tool for diagnosis and assessment of treatment outcome has been delayed mainly because of the lack of a universally accepted standardized methodology. The urodynamic parameters in need of standardization for measurement of VLPP include urethral catheter size, zeroing of the transducer, patient position, bladder volume, type of stress, and timing of measurement. Such standardization likely will allow for further validation of VLPP and its use in distinguishing the right treatment options for the correction of stress urinary incontinence.

Magnetic resonance imaging detection of symptomatic noncommunicating intraurethral wall diverticula in women.

PURPOSE: We documented the merit of endorectal coil magnetic resonance imaging (MRI) for detecting intraurethral wall diverticula in women. MATERIALS AND METHODS: We report on 3 women with a long-standing history of urinary frequency, urgency and voiding dysfunction who had been treated unsuccessfully for other etiologies. RESULTS: MRI of the urethra revealed noncommunicating intraurethral wall diverticula, which were excised. CONCLUSIONS: Urethral MRI should be considered in women with lower urinary tract symptoms secondary to a suspected urethral pathology.

Computer modeling of prostate biopsy: tumor size and location--not clinical significance--determine cancer detection.

PURPOSE: Sampling error is an inherent problem of prostate biopsy, and the determination of clinical significance based on biopsy results is problematic. We quantify the dimensions of these problems by computer simulation. MATERIALS AND METHODS: We constructed 3-dimensional solid computer models of 59 autopsy prostates containing clinically undetected prostate cancer, and performed simulations of the standard prostate biopsy method. RESULTS: Biopsy simulation detected 19 tumors from the 59 prostates, the majority of which were in the most accessible portion of the prostate, the posterior peripheral zone. Using 0.5 cc or greater tumor volume or less than 0.5 cc and Gleason sum 7 or greater as criteria of significance, the model detected 58% (11 of 19) significant tumors and 20% (8 of 40) insignificant tumors. With 0.25 cc or greater tumor volume or less than 0.25 cc and Gleason sum 7 or greater as criteria 15 of 29 significant (52%) and 4 of 30 insignificant (13%) tumors were detected. Among significant tumors defined by either volume criterion there was a statistical difference between detected and undetected tumors in terms of mean tumor volume and mean ratio of tumor volume-to-prostate volume. Among insignificant tumors defined by either criterion there was no such difference. CONCLUSIONS: As much as 20 to 40% of currently detected prostate cancer may be histologically insignificant, as 4 of 19 cancers were detected when 0.25 cc was used as volume determinant of clinical significance and 8 of 19 were detected when 0.5 cc volume was used. These tumors are detected randomly. On the other hand, perhaps only one-half to three-fourths of clinically significant prostate cancers are being detected, and then only because the volume and anatomic location make them hard to miss.

Computer simulation of the probability of detecting low volume carcinoma of the prostate with six random systematic core biopsies.

OBJECTIVES: Six random systematic core biopsies (SRSCB) of the prostate (biopsies from apex, middle, and base of each lobe) have been commonly used in detection of prostate carcinoma. The objective of this study was to verify the validity of the SRSCB technique in detecting cancer in prostates with low-volume tumor (less than 6 cc). METHODS: We developed a computer model of the prostate to simulate the SRSCB technique. The data for development of this model were taken from 159 radical prostatectomy specimens in which 112 patients had tumor volumes measured and in which 91 prostates had tumors with volumes less than 6 cc (by whole-mount sectioning). RESULTS: The simulation shows that only 20.3% of the simulated prostates, with total aggregate tumor volume between 0.034 and 5.1 cc, had a tumor distribution for which the SRSCB technique has a 95% probability of detecting the tumor. In fact, 26.8% had a tumor distribution that was completely disjointed from the six recommended biopsy regions. To compare these results with other possible occurrence, various biases for the angle of biopsy and the distribution of cancer foci were incorporated into the model. Study results should be viewed with the understanding that any simulated model has its limitations. In our simulated model, the shape of the simulated tumor foci (spherical) does not represent all the possible shapes of prostate cancer. However, these results indicate that detection of cancer with biopsies taken from the apex, middle, and base of each lobe of a prostate with tumor volumes of less than 6 cc may not be as effective as it is in prostates with larger tumor volumes or patients with an abnormal digital rectal examination. The study of bias models suggests that the distributional pattern of cancerous foci can have a significant impact on the effectiveness of a given biopsy strategy. CONCLUSIONS: We concluded that future attempts to improve systematic biopsy strategies for detection of low-volume cancer should include biomechanical characteristics of prostate cancer, including gland volume and tumor distribution. Driven by the conclusions from this idealized model, we have developed a three-dimensional model of the prostate gland from its whole-mount histologic maps. It is anticipated that this continuing investigation will lead to realistic guidelines for improving biopsy techniques.

A 3-D reconstruction algorithm for interpolation and extrapolation of planar cross sectional data.

A three dimensional (3-D) reconstruction algorithm utilizing both linear interpolation and linear extrapolation was developed for the study of human prostatic cancer. The algorithm was validated by comparing the volumes and shapes of original to reconstructed objects. Synthetic objects of known geometry and wax models with shapes characteristic of prostatic carcinomas were assessed with standard planimetry and by the digital interpolation-extrapolation method. Volume and multifocality measurements obtained by reconstructing excised prostate glands using histologic maps obtained from whole-mount sections were tested. The new algorithm provided greater accuracy in determining tumor volumes than conventional methods. This model provides a basis for mathematical analysis of prostate cancer lesions.

Benign prostatic disease. A growing challenge in the 1990s.

All of your male patients may one day be concerned with the prospect of prostatic disease. How can you as a primary care physician best approach evaluation and treatment of these disorders? Drs Daneshgari and Crawford provide the information you need to know about recognition and management of benign prostatic hyperplasia and common types of prostatitis.

Endocrine therapy of advanced carcinoma of the prostate.

Increasing evidence suggests that growth of the prostatic tissue is regulated by a network of hormones and growth factors, in which androgens play the prominent role. Hormonal manipulation remains the core of treatment for locally advanced and metastatic prostate cancer. Achievement of a complete androgen blockade, by surgical or medical means or a combination of both, offers superior results in palliative management of advanced disease. Management of hormonal refractory cancer, however, remains a challenge to clinicians.

Etoposide in the treatment of hormone-refractory advanced carcinoma of the prostate.

The leading cause of cancer in males in the United States, prostate cancer accounts for 22% of all new cancers, with 132,000 new cases projected to be diagnosed in 1992. While localized prostate cancer can be cured, up to two thirds of patients present with advanced disease. Androgen deprivation remains the mainstay of treatment for advanced prostate carcinoma. Recurrent disease, however, is invariably refractory to further hormone manipulations. The development of hormone-resistant tumor cells may be explained either by a multi-clones theory, by mutation of previously sensitive tumor cell clones, or, most likely, by both mechanisms. Thus, vigorous efforts are needed to develop nonendocrine treatment approaches. Such efforts have been complicated by the difficulty of assessing therapeutic response in patients with prostate cancer, because the typical metastatic bone lesions seen in these patients are difficult to measure accurately and patients seldom have disease in the lung, lymph nodes, or soft tissue. A variety of single chemotherapeutic agents have been tested against recurrent disease, with widely divergent response rates achieved. Trials of chemohormonal therapy have likewise proved disappointing to date. Preliminary results from an ongoing trial of oral etoposide in patients with recurrent prostate cancer are discussed.

Management of regional lymphatic drainage in carcinoma of the penis.

Radical ilioinguinal lymphadenectomy remains the mainstay of treatment for certain genitourinary carcinomas either with the propensity for or with clinical evidence of metastases to the inguinal-pelvic region. The most frequent indication for this procedure in urologic practice is carcinoma of the penis, followed by carcinoma of the urethra, scrotum, and testis with scrotal invasion. This article reviews the anatomy of the inguinal and iliac region and presents a detailed discussion of the surgical technique and its most recent modifications.

Unusual extramedullary relapse of acute lymphoblastic leukemia in a bone marrow transplant patient.

An unusual form of relapse of acute lymphoblastic leukemia is described in a woman who developed a solitary large focal mass of lymphoblasts in her liver and an isolated polypoid lymphoblastic mass in her uterus after bone marrow transplantation, despite continued marrow remission. Extramedullary visceral leukemic relapse in the form of such discreet focal masses is highly unusual and to our knowledge has not been described in this setting. Awareness and recognition of atypical forms of relapse are important since such a diagnosis carries critical therapeutic and prognostic implications.