Role of cystatin C in urogenital malignancy.

Urogenital malignancy accounts for one of the major causes of cancer-related deaths globally. Numerous studies have investigated novel molecular markers in the blood circulation, tumor tissue, or urine in order to assist in the clinical identification of tumors at early stages, predict the response of therapeutic strategies, and give accurate prognosis assessment. As an endogenous inhibitor of lysosomal cysteine proteinases, cystatin C plays an integral role in diverse processes. A substantial number of studies have indicated that it may be such a potential promising biomarker. Therefore, this review was intended to provide a detailed overview of the role of cystatin C in urogenital malignancy.

Management of bone complications in patients with genitourinary malignancies.

Skeletal metastases are common in genitourinary malignancies-including prostate cancer, renal cell carcinoma, and urothelial cancer-and portend significant morbidity and poor prognosis. The presence of skeletal metastases can result in decreased quality of life and increased morbidity. Strategies can be employed to prevent bone-related complications including lifestyle modifications and dietary supplementation. Additionally, pharmacologic agents exist to prevent bone loss and may be appropriate for patients at high risk of fragility-related or skeletal complications, such as pathologic fracture related to bone metastases. Finally, advancement in effective systemic treatments, particularly novel hormone-targeted agents and immunotherapies, may limit the morbidity of advanced disease and delay the onset of skeletal-related complications.

Health-related quality of life of Brazilian children and adolescents with benign and malignant solid tumours: A prospective cohort study during the first year after hospital admission.

INTRODUCTION: This study aims to assess the impact of paediatric benign and malignant solid tumours and its treatment on the health-related quality of life of children and adolescents who were followed up in a Reference Center in Pediatric Oncology in Rio de Janeiro. METHODS: It is a prospective cohort study. Quality of life assessment was performed using the PedsQL™ 4.0 Generic Core Scales and PedsQL™ 3.0 Cancer Module protocols three times: during hospital admission (T1), 6 months after admission (T2) and 1 year after admission (T3). RESULTS: We evaluated 132 patients, 59 men and 73 women, aged 2-17 years. In PedsQL™4.0, the Emotional Functioning scale was the one with the worst scores, while the scores on the Social Functioning scale was the best. In PedsQL™ 3.0, the worst domains were Procedural Anxiety and Worry. Patients with malignant bone tumours had the worst health-related quality of life. The group who received only surgery had better results. Total scores of PedsQL™4.0 and PedsQL™ 3.0 improved between T1 and T3. CONCLUSION: Children and adolescents with malignant and benign neoplasms undergo changes in quality of life as a result of the disease and treatment, but an improvement has been observed over time.

Genitourinary cancer patients have worse baseline semen parameters than healthy sperm bankers.

BACKGROUND: While the spermatotoxic properties of cancer treatments such as chemotherapy and radiation therapy are widely recognized, the effect of malignancy itself on male fertility is not clearly understood. OBJECTIVES: To determine whether malignancy is associated with diminished semen quality prior to spermatotoxic treatment among sperm bankers. MATERIALS AND METHODS: Retrospective database review of de-identified records was obtained for all episodes of sperm banking performed at a cryobank from January 2004 to May 2017 for one of the following reasons: 'future use' (e.g., military deployment and gender reassignment); infertility; benign disease; and malignancy, further categorized as testicular, other genitourinary (GU), solid non-GU, hematologic, or unspecified. Dependent variables of interest were ejaculatory volume, sperm concentration, % motility, and total motile sperm count (TMSC), as well as post-thaw TMSC. RESULTS: A total of 1558 patients met the inclusion criteria. Multivariable regression analysis on log-transformed data controlling for age demonstrated decreased ejaculatory volume and sperm concentration, % motility, and TMSC in the infertility group as compared to the 'future use' group (p < 0.001). Testicular cancer was associated with decreased sperm concentration, TMSC, and post-thaw TMSC (p < 0.001); other GU malignancy was associated with decreased ejaculatory volume (p < 0.001). Benign disease, solid non-GU malignancy, hematologic malignancy, and unspecified malignancy were not associated with decreased parameters. DISCUSSION: In addition to sperm bankers with known fertility issues, sperm bankers with testicular and other GU malignancy had worse baseline semen parameters as compared to individuals pursuing banking for future use. These findings can inform patient counseling and consent prior to sperm banking and disease treatment. CONCLUSION: Individuals with testicular and other GU malignancy who banked spermatozoa before undergoing spermatotoxic therapy demonstrated worse baseline semen parameters as compared to individuals banking spermatozoa for non-medical reasons.

Role of Epstein-Barr Virus and Human Papillomavirus Coinfection in Oral and Anogenital Carcinogenesis: Potential Tumorigenic Pathways.

Epstein-Barr virus (EBV) and human papillomavirus (HPV) have been implicated in 38% of all virus-related cancers. Over the past three decades, both have been detected in anogenital and head-and-neck squamous cell carcinomas (HNSCC), with evidence of involvement in tumor genesis and progression. Very little has been published on HPV/EBV coinfection. In this chapter, we review the literature on the role of these viruses in oral carcinoma and draw parallels with other HNSCCs and anogenital carcinomas, with emphasis on their interplay and potential signaling pathways. EBV infection seems to create an environment that favors HPV latency, supporting the claim that EBV is a cofactor in HPV-related carcinomas. In turn, under certain circumstances, HPV appears to be able to induce EBV to switch to the latent or replicative state. The main viral oncogenes expressed in these malignancies are EBNA1, EBNA2, LMP1, EBERs, and the high-risk HPV oncogenes E6 and E7. The most well-documented human proteins involved are p53, pRb, p16INK4a, p19ARF, Myc, E-cadherin, ß-catenin, EGFR, MLH1, and COX-2. These proteins are directly associated not only with viral products but also with one another in the development of malignancy. Knowledge of the molecular machinery behind carcinomas coinfected with HPV and EBV may help understand how these viruses trigger carcinogenesis and subsidize the development of new biomarkers of tumor aggressiveness and prognosis, alternative surrogate virus markers, and possible therapeutic targets.

Fertility concerns in men with genitourinary malignancies: Treatment dilemmas, fertility options, and medicolegal considerations.

BACKGROUND: With increasing genitourinary cancer survivorship in patients of reproductive age, fertility preservation has become a greater focus in the management of these patients. MATERIALS AND METHODS: We performed a review of articles pertaining to male infertility, fertility preservation, and genitourinary cancers. The aim was to review causes of infertility in patients with cancer, current options for fertility preservation, research that may expand preservation options, and ethical as well as medicolegal considerations. RESULTS: There are multiple causes of infertility in male patients with cancer, including the malignancy itself, and the treatments required to achieve a potential cure. Surgery can affect the normal pathways for erection, emission, and ejaculation. Chemotherapy can have a profound negative effect on spermatogenesis by causing chromosomal aberrations, maturation arrest, mutagenesis, and impaired spermatozoa motility. Radiation can cause cellular apoptosis with resultant reduction in spermatogonial stem cells. There are numerous methods to secure fertility before cancer treatment with the aid of cryopreservation ranging from simple patient-provided semen samples to complex sperm retrieval techniques. Research in the field of spermatogenic stem cells may lead to improved treatment options such as autotransplant of stem cells for repopulation of the testes after cancer treatment. CONCLUSIONS: Early discussion of possible fertility effects in patients undergoing genitourinary cancer treatment is critical in this era of increasing survivorship. Although current cancer treatments can cause infertility, there are well-established options for fertility preservation and current research will likely lead to improved treatment options.

Optimal surgical treatment and urological outcomes in boys with pelvic and urogenital rhabdomyosarcomas and soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) of pelvic origin in boys often involve the urogenital organs. The optimal extensiveness of radical surgery has long been an issue of discussion, since exenterative surgeries result in severe urogenital adverse effects. We conducted a retrospective review of patients with pelvic STS treated in two regional center hospitals and assessed the radicality of surgery and the functional outcome of the bladder. PATIENTS: Medical records and surgical reports of nine cases (embryonal rhabdomyosarcoma 6, malignant triton tumor 2, suspected rhabdomyosarcoma 1) treated within 1997-2012 were reviewed. Site of origin was prostate in seven, retroperitoneal in two. Average follow-up period was 96 months. TREATMENT AND OUTCOME: All cases were subjected to neoadjuvant chemotherapy. Response was PR in four, SD in two, and PD in two. Radical surgery resulted in gross total resection in eight, and partial resection in one. Three underwent cystoprostatectomy, two cases underwent prostatectomy, and bladder-preserving tumor resection was carried out in four cases. At the last follow-up, three retained a functional bladder. Two required augmentation cystoplasty with intestinal conduits. CONCLUSIONS: The majority of the on-going clinical trials recommend conservative surgery for bladder/prostate rhabdomyosarcoma, and to preserve the bladder function particularly in chemosensitive tumors. Some other groups, however, advocate the importance of radical surgery to prevent local relapse. These reports include heterogenous group of patients in the cohort, and therefore it is difficult to draw a conclusion of which approach truly contributes to the survival of the patients better. Future studies should evaluate bladder and sexual function objectively to establish reliable evidence regarding the benefit and adverse effects of different surgical approaches. These data would be informative to optimize the treatment balance for children with pelvic rhabdomyosarcomas.

Evaluación urodinámica en pacientes sometidos a braquiterapia por rabdomiosarcomas genitourinarios / Urodynamic evaluation in patients undergoing brachytherapy for genitourinary rhabdomyosarcoma

Introducción: El rabdomiosarcoma (RMS) es uno de los tumores sólidos pediátricos más frecuentes. Se ha descrito que la braquiterapia es una herramienta prometedora para tratar esta patología, presentando menos secuelas en los tejidos vecinos. Este estudio tiene como propósito objetivar las secuelas de la dinámica vesical, a través de evaluación con estudios urodinámicos (EUD) a pacientes pediátricos sometidos a cirugía conservadora más braquiterapia por RMS de origen uroginecológico.P acientes y Métodos: Revisión de casos de RMS uroginecológicos desde 2004 a 2011, manejados con braquiterapia pre y/o post operatoria, más quimioterapia preoperatoria. Se realiza estudio urodinámico invasivo y/o no invasivo para evaluar secuelas en función miccional. Resultados: Serie de 4 casos de pacientes con RMS genitourinarios sometidos a braquiterapia sola o asociada a cirugía resectiva: 2 de próstata, 1 vaginal y 1 vesical. Los estudios urodinámicos muestran una capacidad vesical disminuida en 1 paciente, mínima disminución en otro y 2 presentan capacidad normal para la edad. La acomodación del detrusor es adecuada en los 4 pacientes y no hay alteraciones en la función esfinteriana. Clínicamente todos los pacientes son continentes y no presentan sintomatología de disfunción miccional. Conclusiones: El RMS genitourinario es un tumor altamente invasivo y secuelante. La braquiterapia ha logrado un nivel de radiación óptimo que se enfoca en el área tumoral sin afectar mayormente tejidos vecinos. Esto implicaría menos probabilidades de producir efectos secundarios en la dinámica vesical. Hemos demostrado en esta serie, con evaluación urodinámica, que estos pacientes con RMS presentan mínimas alteraciones en la evaluación urodinámica y no tienen repercusión clínica post tratamiento. Trabajos futuros están orientados a evaluación urodinámica pre y post braquiterapia.

Introduction: Rhabdomyosarcoma (RMS) is one of the most common pediatric solid tumors. It has been described that brachytherapy is a promising tool to treat this pathology, presenting less sequelae in neighboring tissues. This study aims to objectify alterations in bladder function through evaluation with urodynamic studies (UDS) in pediatric patients undergoing conservative surgery plus brachytherapy due to urogynecological RMS. Patients and Methods: A review of cases of RMS urogynecological from 2004-2011, managed with pre and / or post-operative brachytherapy, and preoperative chemotherapy. Invasive and / or noninvasive Urodynamic Studies are performed to assess sequelae in voiding function. Results: A series of 4 cases of genitourinary RMS patients undergoing brachytherapy alone or combined with resection surgery: 2 prostate cases, 1 vaginal and 1 bladder case. Urodynamic studies show a decreased bladder in 1 patient, minimal decrease in another and 2 show normal capacity for the patients age. Detrusor compliance is adequate in the 4 patients and there are no alterations in sphincter function. Clinically all patients are continent and show no symptoms of voiding dysfunction. Conclusions: Genitourinary RMS are a highly invasive and invalidating tumor. Brachytherapy achieves optimal radiation level that focuses on the tumor area without greatly affecting neighboring tissues.This could imply less likelyhood to cause side effects in bladder dynamics. We have shown in this series, with urodynamic evaluation, that these patients with RMS have minimal alterations in urodynamic Studies and have no post-treatment clinical impact. Future work is aimed at evaluating urodynamics before and after brachytherapy.

Fetal intra-abdominal tumors: assessment of spectrum, accuracy of prenatal diagnosis, perinatal outcome and therapy at a tertiary referral center.

OBJECTIVE: To describe the varieties and ultrasound characteristics of prenatally diagnosed fetal abdominal tumors and to scrutinize the accuracy of prenatal diagnosis as well as the postnatal outcome and therapy of affected pregnancies. STUDY DESIGN: Retrospective study of 354 fetuses found to have abdominal tumors on prenatal sonogram, identified from 1993 to 2009 at a tertiary referral center for prenatal medicine. The cohort was classified into subgroups according to the sonographic appearance of the fetal tumor and the affected anatomic structure (urinary, gastrointestinal and genital tracts and other locations). Sensitivity, specificity, positive predictive value and false-positive rate of ultrasonography in identifying the system of origin were calculated. Relationships between relevant outcome domains and the different subgroups were assessed using the chi-square test and Fisher's exact test. RESULTS: Our cohort comprised 222 urinary tract lesions, 37 genital tract lesions, 80 gastrointestinal lesions and 15 tumors of other origins. The mean gestational age at diagnosis was 26+0 wks. The prenatally established diagnosis was exactly concordant with postnatal findings in 88.9%. Sensitivity, specificity, positive predictive value and false-positive rate of ultrasonography in identifying the system of origin (urinary, gastrointestinal, genital tracts and other locations) were 98.3%, 97.6%, 92.6% and 2.4%, respectively. The favorable postnatal outcome rate was highest among fetuses with genital tract lesions (95%) and lowest among those with tumors of the urinary tract (62%, p=<0.001). Twenty per cent of tumors regressed spontaneously, mostly gastrointestinal tumors (36%, p=<0.001). In 75/354 cases (21%) the parents opted to terminate the pregnancy: intra-uterine fetal demise and neonatal death were each noted in 4%. Prenatal therapy was performed in 24 of 354 cases (7%) and postnatal surgery in 64 cases (18%). CONCLUSION: The majority of fetal abdominal anomalies were accurately diagnosed and the vast majority of affected fetuses had a favorable outcome, some tumors even resolved with advancing pregnancy. Pre- and post-natal invasive surgical interventions were mandatory in only a small number of cases.

Pleomorphic malignant fibrous histiocytoma/undifferentiated high-grade pleomorphic sarcoma of the scrotum in a patient presenting as fournier gangrene: a case report.

Pleomorphic malignant fibrous histiocytoma (MFH), also known as undifferentiated high-grade pleomorphic sarcoma according to the latest World Health Organization classification, is a diagnosis of exclusion and extremely rare in adult scrotal/paratesticular region. Clinical presentation of scrotal/paratesticular pleomorphic MFH is usually a painless and gradual scrotal swelling. We report a case of scrotal MFH in a 63-year-old man who presented as Fournier gangrene after 10-month painful scrotal swelling and multiple procedures. The specimen of emergent debridement was submitted for pathologic and bacteriologic examination. Microscopically, the lesion had marked architectural and cytologic pleomorphism. The neoplastic cells were positive for vimentin, but negative for all lineage-specific markers. Fluorescence in-situ hybridization showed an aneuploid karyotype and negative results for lipomatous tumor abnormalities. Bacterial cultures of the specimen showed extensive growth of virulent polymicrobes. The diagnosis of scrotal/paratesticular pleomorphic MFH with concurrent Fournier gangrene was made. Thoracic computed tomography scan showed bilateral multiple pulmonary nodules. The patient died 1 month later.

Hyaluronan and hyaluronidase in genitourinary tumors.

Genitourinary cancers are the most frequently diagnosed cancers in men and the fifth most common in women. Management of disease through accurate and cost effective early diagnostic markers, as well as identification of valid prognostic indicators, has contributed significantly to improved treatment outcomes. In this review, we will discuss the function, regulation and clinical utility of hyaluronan (HA), genes encoding its metabolic enzymes and receptors that mediate its cellular effects. Specific HA synthase (HAS) and hyaluronidase (HAase) genes encode the enzymes that produce HA polymers and oligosaccharides, respectively. Differential effects of these enzymes in progression of genitourinary tumors are determined by the relative balance between HAS and HAase levels, as well as the distribution of receptors. The genes are regulated in a complex fashion at the transcriptional and post-translational levels, but also by epigenetic events, alternative mRNA splicing, and subcellular localization. Importantly, the major tumor-derived HAase enzyme, HYAL-1, either alone or together with HA, is an accurate diagnostic and prognostic marker for genitourinary tumors.

Pediatric genitourinary tumors.

PURPOSE OF REVIEW: We will review the recent (2006/2007) literature on pediatric genitourinary tumors. RECENT FINDINGS: The WTX gene is now the most common known gene mutation in Wilms' tumor. It acts as a tumor suppressor gene and may play a role in other malignancies. Current clinical trials have incorporated the loss of heterozygosity of 1p and 16q along with age, tumor size, stage, and response to therapy to risk stratify therapy. The PAX3-FOX01 gene fusion and the IGF-1R-signaling and mTOR-signaling pathways are implicated in rhabdomyosarcoma biology, and hence are promising therapeutic targets for this tumor. SUMMARY: Progress is being made in understanding the pathogenesis of genitourinary tumors in children, and the prognosis for these children continues to improve. Current treatment strategies are focused on improving event-free survival while decreasing late effects from therapy.

Port site metastases.

PURPOSE OF REVIEW: The aim of this article is to provide an overview of the incidence, pathophysiology, risk factors and possible methods of reducing the risk of port site metastases following uro-oncological procedures. RECENT FINDINGS: To our knowledge, 28 cases of port site metastasis have been reported in the urologic literature. There has been an increased interest in the use of intraperitoneal instillation of various tumoricidals in order to reduce the risk of port site seeding. SUMMARY: The risk of port site metastases remains low, provided that surgeons rigorously adhere to the principles of oncological surgery.

Persistent uroplakin expression in advanced urothelial carcinomas: implications in urothelial tumor progression and clinical outcome.

As the terminal differentiation products of human urothelium, uroplakins (UPs) would be expected to diminish during urothelial tumorigenesis. Surprisingly, recent studies found UPs to be retained even by well-advanced urothelial carcinomas, suggesting that the loss of UPs does not strictly parallel urothelial transformation. Little is known, however, about whether the status of UPs is associated with a particular pathologic parameter, the tumor's biological behavior, or patient outcome. Here we assessed UP expression by immunohistochemistry on tissue arrays from 285 patients with bladder urothelial carcinomas or nontumor conditions. UPs were expressed in all 9 normal urothelial specimens, 63 of 74 (85%) patients with non-muscle-invasive urothelial carcinomas on transurethral resection, 104 of 202 (51.5%) patients who underwent radical cystectomy for advanced urothelial carcinomas, and 33 of 50 (66%) lymph node metastases. Normally associated with urothelial apical surface, UPs were localized aberrantly in tumors, including microluminal, basal-laminal, cytoplasmic, or uniform patterns. In non-muscle-invasive diseases, there was no association between UP expression and disease recurrence, progression, or mortality. In contrast, in invasive diseases, absent UP expression was significantly associated with advanced pathologic stage, lymph node metastases, disease recurrence, and bladder cancer-specific mortality (P = .042, P = .035, P = .023, and P = .022, respectively) in univariate analyses. Furthermore, UP status was independent of key cell-cycle regulators, including p53, pRb, p27, and cyclin D1, thus excluding a functional link between these 2 groups of proteins. Our data demonstrate for the first time that persistent UP expression is associated with a favorable clinical outcome and that UPs may be used as adjunct markers for predicting the prognoses of patients with invasive and metastatic bladder carcinomas. Our results also suggest that UP-positive and -negative carcinomas have different clonal origins or may be derived from different cancer stem cells.

Cyclooxygenase-2 as a potential target in the prevention and treatment of genitourinary tumors: a review.

PURPOSE: Recent years have seen a dramatic expansion in our discovery and knowledge of the molecular mechanisms of cancer development and progression. The discovery and elucidation of prostaglandin pathways, in particular the molecular and clinical role of cyclooxygenase (COX)-2 function, has had important application to neoplasms. Current understanding of the role of COX-2 activity and, thereby, the potential clinical usefulness of COX-2 specific inhibitors as they apply to urological oncology are discussed. MATERIALS AND METHODS: The discovery of prostaglandin pathways, the molecular and clinical role of COX-2 function, and the corresponding application to neoplasms were reviewed in the scientific literature (MEDLINE from 1960 to the present). In particular, a thorough review of the current literature and recent abstract presentations at scientific meetings was done regarding the potential role of COX-2 in urological cancers (MEDLINE from 1960 to the present, and American Urological Association and American Society of Clinical Oncology annual meeting abstracts from1998 to the present). RESULTS: Decreased apoptosis, increased angiogenesis and immunosuppression are just some of the known sequelae of COX-2 over expression and each effect may have an important role in tumor formation and progression. Preclinical research and pilot clinical studies in urological oncology, in particular prostate, bladder and kidney cancer, have proved to be quite promising to date. CONCLUSIONS: Currently we are just beginning to understand the molecular mechanisms and clinical effects of COX-2 function and inhibition, and the potential for COX-2 specific inhibitors to affect potentially tumor biology and growth and, thereby, serve as antitumor drugs with therapeutic and chemopreventive roles for urological cancers. The absence of complete scientific understanding in these areas provides a generous opportunity for innovative and important scientific study.

Heat shock proteins in the genitourinary system.

Heat shock proteins are ubiquitous molecules that are expressed in all living organisms in response to stress. They have two specific roles: protection against cell damage and modulation of the immune response. Recent studies have dramatically increased our knowledge and understanding of the role of heat shock proteins in the genitourinary system. This review uses a Medline approach to examine the current literature.

Heat shock proteins: their role in urological tumors.

PURPOSE: Heat shock proteins are ubiquitous molecules that are expressed in response to stress in all living organisms. The 3 important roles in regard to cancer development that have also been described are the regulation of apoptosis, modulation of the immune response and drug resistance. MATERIALS AND METHODS: Recent studies have dramatically increased our current knowledge and understanding of the role of heat shock protein in cancer. We used a MEDLINE approach to examine the past and current literature. RESULTS: The roles of heat shock protein in relation to urological tumors, namely those of the prostate, bladder, kidney and testis, are diverse. There are possible sites for heat shock protein modifications that may lead to new therapeutic approaches to urological cancer. CONCLUSIONS: The possibility of treating patients with vaccines earlier in the disease course may stimulate research.