Clinical outcome in metastatic prostate cancer after primary radiotherapy.

PURPOSE: To describe a local radio-oncological treatment for patients with prostate cancer that metastasized to either the lymph nodes or distant regions. METHODS AND MATERIALS: We included 133 patients with prostate cancer that displayed either distant metastases (DM) or lymph node metastases alone (NM) and were treated between 2004 and 2019. All patients underwent computed tomography and a bone scan or 18F- or prostate-specific membrane antigen-targeted positron emission tomography. Patients received local external beam radiation therapy to the prostate to achieve local control (60-81.4 Gy to the prostate, and 45-50.4 Gy to pelvic lymph nodes), with either the 3D conformal (4-field box) or volumetric modulated arc therapy technique. A urologist prescribed additional therapy. RESULTS: We included 51 patients with DM and 82 patients with NM. The mean follow-up was 42 months for all patients. The groups were similar in T stage, initial prostate-specific antigen, histology, androgen deprivation therapy, age, treatment techniques, and prescribed doses, but different in lymph node inclusion and follow-up times. In the NM and DM groups, the 5­year biochemical recurrence-free rates were 52% and 24%, respectively (p < 0.0001); the 5­year disease-specific survival rates were 92% and 61%, respectively (p = 0.001); and the 5­year OS rates were 77% and 48%, respectively (p = 0.01). The groups had similar acute and late gastrointestinal and genitourinary side effects, except that late genitourinary side effects occurred significantly more frequently in the NM group (p = 0.01). CONCLUSIONS: DM was associated with significantly worse outcomes than NM. The long-term survival of patients with metastatic prostate cancer was low.

In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo: Part II: Pathology: Part II: Pathology.

It is clear from Part I of this series that extracellular vesicles (EVs) play a critical role in maintaining the homeostasis of most, if not all, normal physiological systems. However, the majority of our knowledge about EV signalling has come from studying them in disease. Indeed, EVs have consistently been associated with propagating disease pathophysiology. The analysis of EVs in biofluids, obtained in the clinic, has been an essential of the work to improve our understanding of their role in disease. However, to interfere with EV signalling for therapeutic gain, a more fundamental understanding of the mechanisms by which they contribute to pathogenic processes is required. Only by discovering how the EV populations in different biofluids change-size, number, and physicochemical composition-in clinical samples, may we then begin to unravel their functional roles in translational models in vitro and in vivo, which can then feedback to the clinic. In Part II of this review series, the functional role of EVs in pathology and disease will be discussed, with a focus on in vivo evidence and their potential to be used as both biomarkers and points of therapeutic intervention.

Prospective validation of stringent dose constraints for prostatic stereotactic radiation monotherapy: results of a single-arm phase II toxicity-oriented trial.

PURPOSE: There are no safety-focused trials on stereotactic body radiotherapy (SBRT) for localized prostate cancer. This prospective 3­year phase II trial used binomial law to validate the safety and efficacy of SBRT with stringent organ at risk dose constraints that nevertheless permitted high planning target volume doses. METHODS: All consecutive ≥ 70-year-old patients with localized prostate adenocarcinoma who underwent SBRT between 2014 and 2018 at the National Radiotherapy Center in Luxembourg were included. Patients with low Cancer of Prostate Risk Assessment (CAPRA) scores (0-2) and intermediate scores (3-5) received 36.25 Gy. High-risk (6-10) patients received 37.5 Gy. Radiation was delivered in 5 fractions over 9 days with Cyberknife-M6™ (Accuray, Sunnyvale, CA, USA). Primary study outcome was Common Terminology Criteria for Adverse Events version 4 (CTCAEv4) genitourinary and rectal toxicity scores at last follow-up. Based on binomial law, SRBT was considered safe in this cohort of 110 patients if there were ≤ 2 severe toxicity (CTCAEv4 grade ≥ 3) cases. Secondary outcomes were biochemical progression-free survival (bPFS) and patient quality of life (QOL), as determined by the IPPS and the Urinary Incontinence QOL questionnaire. RESULTS: The first 110 patients who were accrued in a total cohort of 150 patients were included in this study and had a median follow-up of 36 months. Acute grade ≥ 3 toxicity never occurred. One transient late grade 3 case was observed. Thus, our SBRT program had an estimated severe toxicity rate of < 5% and was safe at the p < 0.05 level. Overall bPFS was 90%. QOL did not change relative to baseline. CONCLUSION: The trial validated our SBRT regimen since it was both safe and effective.

Telocytes of the male urogenital system: Interrelationships, possible functions, and pathological implications.

The male urogenital system is composed of the reproductive system and the urinary tract; they have an interconnected embryonic development and share one of their anatomical components, the urethra. This system has a highly complex physiology deeply interconnected with the circulatory and nervous systems, as well as being capable of adapting to environmental variations; it also undergoes changes with aging and, in the case of the reproductive system, with seasonality. The stroma is an essential component in this physiological plasticity and its complexity has increased with the description in the last decade of a new cell type, the telocyte. Several studies have demonstrated the presence of telocytes in the organs of the male urogenital system and other systems; however, their exact function is not yet known. The present review addresses current knowledge about telocytes in the urogenital system in terms of their locations, interrelationships, possible functions and pathological implications. It has been found that telocytes in the urogenital system possibly have a leading role in stromal tissue organization/maintenance, in addition to participation in stem cell niches and an association with the immune system, as well as specific functions in the urogenital system, lipid synthesis in the testes, erythropoiesis in the kidneys and the micturition reflex in the bladder. There is also evidence that telocytes are involved in pathologies in the kidneys, urethra, bladder, prostate, and testes.

Primary Amyloidosis of the Genitourinary Tract.

CONTEXT.­: Amyloidosis is caused by the deposition of misfolded proteins as insoluble eosinophilic material in the extracellular tissues of the body, leading to impairment of organ function. It can be systemic or localized. Localized genitourinary tract amyloidosis is rare and can be incidentally seen; however, in some cases, it can be the only presenting disease. OBJECTIVE.­: To review the clinical presentation and pathologic findings related to primary amyloidosis of the urogenital system and highlight some of the associated pathologic findings based on our personal experience. DATA SOURCES.­: Published peer-reviewed literature and personal experience of the senior author. CONCLUSIONS.­: Primary localized amyloidosis within the urogenital tract can present as a neoplastic process and may be clinically and radiologically considered as a mass. Awareness of primary amyloidosis by pathologists and clinicians is required for accurate diagnosis and proper patient management.

Practical Molecular Testing in a Clinical Genitourinary Service.

CONTEXT.­: Molecular testing is increasingly playing a key role in the diagnosis, prognosis, and treatment of neoplasms of the genitourinary system. OBJECTIVE.­: To provide a general overview of the clinically relevant molecular tests available for neoplasms of the genitourinary tract. DATA SOURCES.­: Relevant medical literature indexed on PubMed. CONCLUSIONS.­: Understanding of the molecular oncology of genitourinary neoplasms is rapidly advancing, and the pathologist must be aware of the practical implications of molecular testing. While many genomic abnormalities are not yet clinically relevant, there is an increasing library of ancillary tests that may guide diagnosis, prognosis, and/or treatment of many neoplasms. Recurrent genomic abnormalities have been identified in many types of renal cell carcinoma, and some types of renal cell carcinoma are specifically defined by the molecular abnormality. Two major routes of developing urothelial carcinoma have been molecularly described. Recurrent translocations involving ETS family genes are found in approximately half of prostate cancer cases. Testicular germ cell tumors typically harbor i(12p). Penile neoplasms are often high-risk human papillomavirus-driven cancers. Nonetheless, even as genitourinary neoplasms are increasingly better understood at the molecular level, further research with eventual clinical validation is needed for optimal diagnosis, prognosis, and treatment of aggressive malignancies in the genitourinary tract.

Effects of secondary biological treatment plant effluent administration, as drinking water, to rats' urogenital system in relation to cadmium and lead accumulation.

The aim of this study was to examine the effect of the secondary biological treatment plant effluent administration on the kidneys, urinary bladder, and testis of Wistar rats in relation to lead (Pb) and cadmium (Cd) accumulation, since such an effluent is used for irrigation of edible plants. Male Wistar rats, randomly assigned into 5 groups, were treated with domestic sewage effluent (DSE) for 24 months. Cadmium and lead concentrations in the DSE, rats' tissues, and urine were estimated by means of atomic spectroscopy. Lead was rapidly accumulated in high amounts in rats' kidney and to a lesser extent in the testis whereas Cd concentration was raised in all tissues examined. Deposition of Cd and Pd in the kidney of the rats resulted in profound damage over time. The results showed that long-term administration to DSE as drinking water exposes living organisms to urogenital stress related to heavy metal concentration and pH of the effluent.

Overall systematic approach to sepsis damages on urogenital tissues: protective power of lacosamide.

PURPOSE: The aim of the study was to evaluate the harmful effects of sepsis on the urogynecological tissues and the ability of Lacosamide (LCM) on Lipopolysaccharide (LPS)-induced cytokine production, oxidative stress and apoptotic pathways, in the experimental rat sepsis model. METHODS: Twenty-four female Wistar albino rats (12 months old) were divided into 3 groups as follows: control group (Group I) (0.1 ml/oral and i.p. saline, single dose), sepsis group (Group II) (5 mg/kg LPS, i.p. single dose) and sepsis + LCM group (Group III) (5 mg/kg LPS, i.p. single dose and 40 mg/kg LCM). Six hours after the last LPS administration, the animals were sacrificed. Subsequently, the analyses of urogenital tissues total oxidant/antioxidant status, histopathological and immunohistochemical analyses were performed. RESULTS: Total oxidant capacity (TOC) and oxidative stress index (OSI) values in the urogenital tissues were increased in the urogenital tissues in Group II [Total antioxidant capacity (TAC) was decreased] compared to group I (p < 0.05). LCM improved these values (p < 0.05). The immunohistochemical markers (Tumor Necrosis Factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), heat shock protein 70 (HSP-70), C-reactive protein (CRP), Malondialdehyde (MDA) were significantly increased in Group II (p < 0.001). With the administration of LCM (Group III), the expressions of above-mentioned markers were markedly decreased (p < 0.001). Marked hyperemia and slight hemorrhages with neutrophil leukocyte infiltrations were seen histopathologically in Group II. LCM treatment ameliorated the pathological findings. CONCLUSION: These findings demonstrated that sepsis caused oxidative stress, apoptosis and inflammation in the urogenital tissues. We revealed that LCM ameliorated the damage caused by sepsis in urogenital tissue.

Topical estrogen prescribing patterns for urogenital atrophy among women with breast cancer: results of a national provider survey.

OBJECTIVE: The aim of the study was to evaluate knowledge, attitudes, and practice patterns of physicians prescribing topical estrogen for women with urogenital atrophy and a history of breast cancer. METHODS: A cross-sectional survey of breast surgeons, urogynecologists, and gynecologists was distributed via their professional societies: the American Society of Breast Surgeons (ASBrS), the American Urogynecologic Society (AUGS), and the Society of Gynecologic Surgeons (SGS). Providers reported level of comfort prescribing vaginal estrogen for urogenital symptoms for women with different categories of breast cancer and current treatment: estrogen receptor (ER) negative, ER positive no longer on endocrine therapy, and ER positive currently on adjuvant endocrine therapy. General knowledge questions assessed agreement on a 5-point Likert scale to statements about vaginal estrogen safety and pharmacology. RESULTS: A total of 820 physicians completed the survey: 437 responses from the ASBrS (response rate, 26.7%), 196 from AUGS (15%), and 187 from SGS (44.5%). The majority of physicians (84%), regardless of specialty, felt comfortable prescribing vaginal estrogen to women with a history of ER-negative cancer: 65.7% felt comfortable prescribing for women with ER-positive breast cancer no longer on endocrine therapy; 51.3% for women on an aromatase inhibitor; and 31.4% for women on tamoxifen. Urogynecologists were significantly more comfortable than breast surgeons prescribing vaginal estrogen for the lowest risk patients, whereas breast surgeons had the highest level of comfort for women currently on endocrine therapy. CONCLUSIONS: This study highlights heterogeneity in practice patterns both within and across specialties. The clinical variation seen in this study suggests providers may benefit from increased knowledge regarding vaginal estrogen.

Chlamydia trachomatis bacterial load, estimated by Cq values, in urogenital samples from men and women visiting the general practice, hospital or STI clinic.

BACKGROUND: The bacterial load of Chlamydia trachomatis (CT) is assumed to play a role in transmission and sequelae. We assessed urogenital CT cycle quantification (Cq) values, as an indicator for CT load, of men and women diagnosed by general practitioners (GPs), hospital physicians and the STI clinic. METHODS: Urogenital CT-positive samples (n = 2,055 vaginal swabs, n = 77 cervical swabs, n = 1,519 urine samples and n = 19 urethral swabs) diagnosed by GPs, hospital physicians and the STI clinic from the Maastricht Medical Microbiology Laboratory were included (2012-2016). The outcome measure 'urogenital Cq values' was used as an inversely proportional measure for CT load. Among all patients, multivariate linear regression analyses were used to assess primary determinants for mean urogenital Cq values, stratified by sex. Additional clinical determinants were assessed among STI clinic patients. RESULTS: In men, mean urogenital Cq values were similar between GPs, hospital physicians and the STI clinic (32.7 and 33.5 vs. 32.7; p>0.05). Women visiting the GP had lower urogenital Cq values than women visiting the STI clinic (30.2 vs. 30.9; p = <0.001). Women visiting the hospital had higher urogenital Cq values than women visiting the STI clinic (32.4 vs. 30.9; p = <0.001). Among STI clinic women, urogenital Cq values were lower in women with concurrent anorectal CT and in rectally untested women compared to anorectal CT-negative women (30.7 and 30.6 vs. 33.9; p = <0.001). CONCLUSION: Men visiting different STI care providers had similar urogenital Cq values, which could be an indicator for similar CT loads. The lower Cq values of women visiting the GP compared to women visiting the STI clinic could be an indicator for higher CT loads and likely higher transmission potential. Notably, urogenital Cq values of STI clinic women were much lower (>3 Cq) when STI clinic women also had anorectal CT. This finding could indicate higher urogenital CT loads and likely higher chances of transmission and sequelae.

Klebsiella Pneumoniae Visceral Organ Abscesses - Clinical Characteristics.

INTRODUCTION: In recent years, Klebsiella pneumonia (KP) has emerged as the predominant cause of pyogenic liver abscess in Asia. KP - as the causative microorganism in other visceral organ abscesses-is less described. In this study, we seeked to describe the clinical characteristics of KP visceral organ abscesses in our institution and evaluated the prescription practices of physicians with regard to antibiotic therapy. MATERIALS AND METHODS: A retrospective analysis of patients with culture positive (blood or abscess aspirate) KP visceral organ abscesses from May 2014 to April 2016 requiring hospitalisation in Changi General Hospital was conducted. RESULTS: A total of 140 adult patients with KP visceral organ abscesses were identified. The commonest site of involvement was the liver (77.9%), followed by genitourinary tract (20.7%). Diabetic patients were more likely to have liver abscesses, genitourinary abscesses, abscesses in 2 or more organs, genitourinary disease with abscess formation outside of the genitourinary tract, and endovascular infection. Patients with extended spectrum beta-lactamase producing KP, were more likely to have an obstructive lesion related to the site of the abscess. Overall mortality rate was 7.1%. Amongst survivors, the mean total duration of parenteral antimicrobial therapy was 2.5 weeks before switching to oral antimicrobial agents. CONCLUSION: Genitourinary tract is the commonest extra-hepatic site for visceral organ abscess in KP infections. Parenteral to oral switch of antimicrobial agents appears to be a safe and effective treatment option.

Isopsoralen induces different subchronic toxicities and metabolomic outcomes between male and female Wistar rats.

Isopsoralen is a major active and quality-control component of Fructus Psoraleae, but lacks a full safety evaluation. We evaluated the oral toxicity of isopsoralen in Wistar rats treated for 3 months at doses of 0, 3.5, 7.0, and 14 mg/kg. Additionally, the plasma metabolomics of isopsoralen in male and female rats treated for 3 months at doses of 0 and 14 mg/kg were investigated by gas chromatography-mass spectrometry. Many abnormalities were observed in the isopsoralen-treated rats, including suppression of body weight gain, and changes in serum biochemical parameters and visceral coefficients. Histopathological changes in liver, pancreatic, and reproductive system tissues were also observed in the isopsoralen-treated rats. The metabolomic analyses showed alterations in many metabolites (19 in female rats; 28 in male rats) after isopsoralen administration. The significant changes in these metabolites revealed metabolomic alterations in the isopsoralen-treated rats, especially in amino acid metabolism regardless of sex, including phenylalanine, tyrosine, and tryptophan biosynthesis and glycine, serine, and threonine metabolism. Furthermore, fatty acid metabolism comprised the main affected pathways in female rats, while lipid metabolism and energy metabolism were the main affected pathways in male rats.

Impact of bladder volume on acute genitourinary toxicity in intensity modulated radiotherapy for localized and locally advanced prostate cancer.

BACKGROUND AND PURPOSE: To evaluate the effect of changes in bladder volume during high-dose intensity-modulated-radiotherapy (IMRT) of prostate cancer on acute genitourinary (GU) toxicity and prospectively evaluate a simple biofeedback technique for reproducible bladder filling with the aim of reducing acute GU toxicity. METHODS: One hundred ninety-three patients were trained via a biofeedback mechanism to maintain a partially filled bladder with a reproducible volume of 200-300 cc at planning CT and subsequently at each fraction of radiotherapy. We prospectively analyzed whether and to what extent the patients' ability to maintain a certain bladder filling influenced the degree of acute GU toxicity and whether cut-off values could be differentiated. RESULTS: We demonstrated that the ability to reach a reproducible bladder volume above a threshold volume of 180 cc and maintain that volume via biofeedback throughout treatment predicts for a decrease in acute GU toxicity during curative high-dose IMRT of the prostate. Patients who were not able to reach a partial bladder filling to that cut-off value and were not able to maintain a partially filled bladder throughout treatment had a significantly higher risk of developing ≥grade 2 GU acute toxicity. CONCLUSION: Our results support the hypothesis that a biofeedback training for the patient is an easy-to-apply, useful, and cost-effective tool for reducing acute GU toxicity in high-dose IMRT of the prostate. Patients who are not able to reach and maintain a certain bladder volume during planning and treatment-two independent risk factors-might need special consideration.

Comparison of rRNA-based and DNA-based nucleic acid amplifications for detection of Chlamydia trachomatis, Neisseria gonorrhoeae, and Ureaplasma urealyticum in urogenital swabs.

BACKGROUND: Nucleic acid amplification tests (NAAT) are well-accepted in diagnosis and surveillance of sexually infectious pathogens worldwide. However, performance differences between a RNA-based NAAT and DNA-based NAAT are rarely reported. This study compares the performances of the RNA-based SAT (simultaneous amplification and testing) assay and the DNA-based quantitative real-time polymerase chain reaction (qPCR) assay. METHODS: A total of 123 urogenital swabs were collected from outpatients with suspected genital infections in our hospital. Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Ureaplasma urealyticum (UU) in these swabs were simultaneously tested by SAT and qPCR. Any swabs were positive in the qPCR assay were further verified by following cloning and sequencing. All statistical analysis was performed using the SPSS software. RESULTS: When the concentrations of CT, NG, or UU were more than 1 × 103 copies/ml, 100% agreements between SAT and qPCR were observed regardless of the pathogen. No discrepancy was found. However, the sensitivity of SAT is significantly higher than qPCR in samples with concentration less than 1 × 103 copies/ml. When tested by SAT and qPCR, 57.14 and 28.57% were positive for CT, 46.15% and 0 were positive for NG, 80% and 0 were positive for UU, respectively. CONCLUSIONS: The SAT assay has better agreements and higher sensitivities when compared with the qPCR assay, and thus could be a better choice for screening, diagnosis, and surveillance of sexually transmitted diseases, especially for CT and NG.

Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause.

OBJECTIVE: The aim of this study is to confirm the local beneficial effects of intravaginal dehydroepiandrosterone (DHEA, Prasterone) on moderate to severe dyspareunia or pain at sexual activity, the most frequent symptom of vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause (GSM). METHODS: In a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial, the effect of daily intravaginal 0.50% DHEA (6.5 mg) (Prasterone, EndoCeutics) was examined on four coprimary objectives, namely percentage of parabasal cells, percentage or superficial cells, vaginal pH, and moderate to severe pain at sexual activity (dyspareunia) identified by the women as their most bothersome vulvovaginal atrophy symptom. The intent-to-treat population included 157 and 325 women in the placebo and DHEA-treated groups, respectively. RESULTS: After daily intravaginal administration of 0.50% DHEA for 12 weeks, when compared to baseline by the analysis of covariance test, the percentage of parabasal cells decreased by 27.7% over placebo (P < 0.0001), whereas the percentage of superficial cells increased by 8.44% over placebo (P < 0.0001), vaginal pH decreased by 0.66 pH unit over placebo (P < 0.0001), and pain at sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = 0.0002). On the other hand, moderate to severe vaginal dryness present in 84.0% of women improved at 12 weeks by 1.44 severity score unit compared to baseline, or 0.27 unit over placebo (P = 0.004). At gynecological evaluation, vaginal secretions, epithelial integrity, epithelial surface thickness, and color all improved by 86% to 121% over the placebo effect (P < 0.0001 for all comparisons with placebo). Serum steroid levels remained well within the normal postmenopausal values according to the involved mechanisms of intracrinology. The only side effect reasonably related to treatment is vaginal discharge due to melting of the vehicle at body temperature and this was reported in about 6% of the participants. CONCLUSIONS: The daily intravaginal administration of 0.50% (6.5 mg) DHEA (Prasterone) has shown clinically and highly statistically significant effects on the four coprimary parameters suggested by the US Food and Drug Administration. The strictly local action of Prasterone is in line with the absence of significant drug-related adverse events, thus showing the high benefit-to-risk ratio of this treatment based upon the novel understanding of the physiology of sex steroids in women.

Impact on genitourinary function and quality of life following focal irreversible electroporation of different prostate segments.

PURPOSE: We aimed to evaluate the genitourinary function and quality of life (QoL) following the ablation of different prostate segments with irreversible electroporation (IRE) for localized prostate cancer (PCa). METHODS: Sixty patients who received primary focal IRE for organ-confined PCa were recruited for this study. Patients were evaluated for genitourinary function and QoL per prostate segment treated (anterior vs. posterior, apex vs. base vs. apex-to-base, unilateral vs. bilateral). IRE system settings and patient characteristics were compared between patients with preserved vs. those with impaired erectile function and urinary continence. Data were prospectively collected at baseline, 3, 6, and 12 months using the expanded prostate cancer index composite, American Urological Association symptom score, SF-12 physical and mental component summary surveys. Difference over time within segments per questionnaire was evaluated using the Wilcoxon's signed rank test. Outcome differences between segments were assessed using covariance models. Baseline measurements included questionnaire scores, age, and prostate volume. RESULTS: There were no statistically significant changes over time for overall urinary (P = 0.07-0.89), bowel (P = 0.06-0.79), physical (P = 0.18-0.71) and mental (P = 0.45-0.94) QoL scores within each segment. Deterioration of sexual function scores was observed at 6 months within each segment (P = 0.001-0.16). There were no statistically significant differences in QoL scores between prostate segments (P = 0.08-0.97). Older patients or those with poor baseline sexual function at time of treatment were associated with a greater risk of developing erectile dysfunction. CONCLUSION: IRE is a feasible modality for all prostate segments without any significantly different effect on the QoL outcomes. Older patients and those with poor sexual function need to be counseled regarding the risk of erectile dysfunction.