A Urine Based Genomic Assay to Triage Patients with Hematuria for Cystoscopy.

PURPOSE: Current clinical guidelines recommend cystoscopy in patients who present with hematuria to rule out a bladder tumor. We evaluated whether our previously developed urine assay was able to triage patients with hematuria for cystoscopy in a large prospective cohort. MATERIALS AND METHODS: A urine sample was collected before cystoscopy and mutation/methylation status of 6 genes was determined on cellular DNA. The existing diagnostic model was validated on this cohort. Logistic regression was applied to investigate other potential variables. The primary end point was the model performance as indicated by the AUC. Secondary end points were sensitivity, specificity and negative predictive value. Clinical usefulness was determined by the net benefit approach. RESULTS: In 838 patients biomarker status could be determined for all genes. Urothelial cancer was observed in 112 patients (98 of 457 in the gross and 14 of 381 in the microscopic hematuria group). Validation of the existing model resulted in an AUC of 0.93. Logistic regression analysis identified type of hematuria as a significant additional variable. Adding type of hematuria resulted in an AUC of 0.95 (96% sensitivity, 73% specificity, 99% negative predictive value). The assay identified all upper tract tumors not visible by cystoscopy (in 6). Net benefit analysis showed that the urine assay should be preferred over current clinical practice. Implementing the urine assay as a triage tool could lead to a 53% reduction in cystoscopies. CONCLUSIONS: The urine assay detected urothelial cancer with a very high accuracy and can be used to triage patients presenting with hematuria for cystoscopy.

Role of Hormonal Treatment in Prostate Cancer Patients with Nonmetastatic Disease Recurrence After Local Curative Treatment: A Systematic Review.

CONTEXT: The relative benefits and harms of hormonal treatment (HT) versus no or deferred HT in patients with nonmetastatic prostate cancer (PCa) relapse after primary curative therapy are controversial. OBJECTIVE: To assess the effectiveness of HT for nonmetastatic PCa relapse, prognostic factors for treatment outcome, timing of treatment, and the most effective treatment strategy to provide guidance for clinical practice. EVIDENCE ACQUISITION: A systematic literature search was undertaken incorporating Medline, Embase, and the Cochrane Library (search ended March 2015). Studies were critically appraised for risk of bias. The outcomes included overall and cancer-specific survival, metastasis-free survival, symptom-free survival, progression to castrate resistance, adverse events, and quality of life. EVIDENCE SYNTHESIS: Of 9687 articles identified, 27 studies were eligible for inclusion (2 RCTs, 8 nonrandomised comparative studies, and 17 case series). The results suggest that only a subgroup of patients, especially those with high-risk disease, may benefit from early HT. The main predictors for unfavourable outcomes were shorter PSA doubling time (<6-12 mo) and higher Gleason score (>7). Early HT may be warranted for patients with high-risk disease. An intermittent HT strategy appears feasible. Most studies had a moderate to high risks of bias. CONCLUSIONS: HT for PCa relapse after primary therapy with curative intent should be reserved for patients at highest risk of progression and with a long life expectancy. The potential benefits of starting HT should be judiciously balanced against the associated harms. PATIENT SUMMARY: This article summarises the evidence on the benefits and harms of hormonal treatment in prostate cancer (PCa) patients in whom the disease has recurred following earlier curative treatment. We found that only a select group of patients with aggressive PCa and a fast rising prostate-specific antigen may benefit from early hormonal treatment (HT), whereas in others HT may be more harmful than beneficial.

Electroejaculation as a method of fertility preservation in boys diagnosed with cancer: a single-center experience and review of the literature.

OBJECTIVE: To evaluate the feasibility of electroejaculation to perform semen cryopreservation in pubertal boys before gonadotoxic therapy and to review the literature on this topic. DESIGN: Retrospective cohort study and review of the literature. SETTING: Academic children's hospital. PATIENT(S): Boys diagnosed with cancer to whom sperm cryopreservation was offered before the start of gonadotoxic therapy. INTERVENTION(S): We studied the outcome of electroejaculation, including patient characteristics, hormone levels, and pretreatment semen parameters. MAIN OUTCOME MEASURE(S): Semen cryopreservation. RESULT(S): Pretreatment semen samples were obtained by masturbation in 106/114 boys with cancer, of which 78/106 were adequate for preservation. Electroejaculation was offered to 11 boys, of which three of 11 samples appeared adequate for preservation. Reviewing all reported electroejaculation cases in children with cancer in the literature, 13/29 (45%) cases were successful. Testosterone levels were higher in patients with successful sperm yield obtained by electroejaculation (median, 8.3 nmol/L [5.2-42.4] in successful harvests, vs. median 1.7 nmol/L [0.01-17.9] in unsuccessful harvests). CONCLUSION(S): Semen cryopreservation should be offered to all pubertal boys diagnosed with cancer. If masturbation fails, electroejaculation can be considered as a useful option for semen cryopreservation and leads to adequate material for cryopreservation in about half of the cases.

Testicular biopsy: clinical practice and interpretation.

Testicular biopsy was considered the cornerstone of male infertility diagnosis for many years in men with unexplained infertility and azoospermia. Recent guidelines for male infertility have limited the indications for a diagnostic testicular biopsy to the confirmation of obstructive azoospermia in men with normal size testes and normal reproductive hormones. Nowadays, testicular biopsies are mainly performed for sperm harvesting in men with non-obstructive azoospermia, to be used for intracytoplasmic sperm injection. Testicular biopsy is also performed in men with risk factors for testicular malignancy. In a subgroup of infertile men, there is an increased risk for carcinoma in situ of the testis, especially in men with a history of cryptorchidism and testicular malignancy and in men with testicular atrophy. Ultrasonographic abnormalities, such as testicular microlithiasis, inhomogeneous parenchyma and lesions of the testes, further increase the risk of carcinoma in situ (CIS) in these men. For an accurate histological classification, proper tissue handling, fixation, preparation of the specimen and evaluation are needed. A standardized approach to testicular biopsy is recommended. In addition, approaches to the detection of CIS of the testis testicular immunohistochemistry are mandatory. In this mini-review, we describe the current indications for testicular biopsies in the diagnosis and management of male infertility.

Gonadal dysfunction in male cancer patients before cytotoxic treatment.

Male patients diagnosed with cancer are often referred for semen cryopreservation before gonadotoxic treatment but often have low semen quality. The aim of this study was to evaluate which type of cancer affects gonadal function and proposes a risk factor for low pre-treatment semen quality. Between January 1983 and August 2006, 764 male cancer patients were referred for semen cryopreservation prior to chemotherapy and radiotherapy. We compared semen characteristics and reproductive hormones between different groups of cancer patients. In addition, we evaluated the role of tumour markers in patients with testicular germ-cell tumours (TGCT) on fertility. Abnormal semen parameters were found in 489 men (64%) before cancer treatment. Patients with TGCT and extragonadal germ-cell tumours had significantly lower sperm concentrations and inhibin B levels than all other patient groups. No semen could be banked in 93 patients (12.2%). Eight hundred and thirty-nine of 927 (90%) produced semen samples were adequate for cryopreservation. Inhibin B in all groups showed to be the best predictor of semen quality. Although pre-treatment raised tumour markers were associated with a decrease in inhibin B and increased follicle stimulating hormone, both predictive for low semen quality; no direct linear association could be found between raised beta-HCG, alfa-fetoprotein and semen quality. Only 1/3 of cancer patients had normal semen parameters prior to cancer treatment. Patients with TGCT and extragonadal GCT have the highest risk for impaired semen quality and gonadal dysfunction at the time of semen cryopreservation.

Effect of childhood cancer treatment on fertility markers in adult male long-term survivors.

BACKGROUND: Although it is accepted that pediatric cancer treatment harbors a risk of gonadal damage, large cohort studies using up-to-date fertility markers are lacking. PROCEDURE: The aim of our study was to evaluate the gonadal toxicity of childhood cancer treatment using fertility markers. We included 248 adult male long-term survivors of childhood cancer. Median age at diagnosis: 5 years, median age at follow-up: 24 years, median follow-up time 18 years. We evaluated patient characteristics, treatment modalities, testicular size, and endocrinological parameters including Inhibin B, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. RESULTS: The median value of Inhibin B in the cancer survivor group was 126 ng/L versus 177 ng/L in the control group (P < 0.001). In the survivors, 67% had Inhibin B levels below the normal reference value of 150 ng/L compared with 26% in the control group (P < 0.05). Inhibin B was the most sensitive discriminator between survivors and controls. Significantly decreased Inhibin B levels and increased FSH levels were found in men treated for Hodgkin and non-Hodgkin lymphoma, acute-myeloid leukemia, neuroblastoma, and sarcoma as compared to other malignancies. Cumulative dosages of procarbazine and cyclophosphamide were the only independent chemotherapy-related predictors for decrease of Inhibin B levels and increase of FSH. Age at time of treatment did not influence post-treatment Inhibin B or FSH levels. CONCLUSIONS: Severe gonadal impairment is a risk in a considerable subgroup of childhood cancer survivors based on current fertility markers like Inhibin B. Males receiving gonadotoxic treatment before puberty are not protected from post treatment gonadal dysfunction.

Heterogeneous distribution of ITGCNU in an adult testis: consequences for biopsy-based diagnosis.

Carcinoma in situ (CIS) of the testis, also referred to as intratubular germ cell neoplasia unclassified (ITGCNU), is currently accepted as the common precursor for all malignant germ cell tumors of adolescents and adults- that is, the seminomatous and nonseminoma cancers. These preinvasive cells have specific cellular characteristics, which can be used for the early diagnosis-routinely done by morphological analysis, sometimes supported by immunohistochemistry-of tissue obtained by an open surgical biopsy. False-negative biopsy results can occur mostly because of the nonrandom distribution of ITGCNU within the testis, misdiagnosis, or suboptimal tissue treatment and analysis. In this article, we demonstrate the potential pitfalls in the diagnosis of ITGCNU. The results support the use of the highly specific and sensitive immunohistochemical marker OCT3/4 for the diagnosis of ITGCNU and provide evidence for the nonrandom distribution of ITGCNU, which is a significant limitation in the diagnosis of this preinvasive lesion.

Semen cryopreservation in pubertal boys before gonadotoxic treatment and the role of endocrinologic evaluation in predicting sperm yield.

OBJECTIVE: To evaluate the feasibility of semen cryopreservation in pubertal boys before they receive gonadotoxic therapy and to identify which pretreatment parameters might predict successful cryopreservation. DESIGN: Retrospective data analysis. SETTING: Tertiary fertility center, academic children's hospital. PATIENT(S): Between 1995 and 2005, 80 boys (median age 16.6 years, range 13.7-18.9 years) consulted the outpatient clinic of andrology for semen cryopreservation before a potentially gonadotoxic treatment. INTERVENTION(S): We assessed the pretreatment semen parameters, hormone levels, and patients' characteristics. MAIN OUTCOME MEASURE(S): Measurement of the number of adolescents able to cryopreserve semen. RESULT(S): Thirteen boys were unable to produce semen by masturbation. In 53 boys semen quality was adequate for cryopreservation. In 14 patients semen analysis did not show motile spermatozoa, and therefore semen cryopreservation could not be performed. Although inhibin B showed a strong correlation with sperm count, no significant difference was found in serum T, inhibin B, LH, and FSH levels in the patients with or without successful sperm yield. Moreover, median age was not different between patients with and without a successful sperm yield. CONCLUSION(S): Semen cryopreservation in boys is a feasible method to preserve spermatozoa before gonadotoxic therapy is started and should be offered to all pubertal boys despite their young age. Serum hormone levels do not predict sperm yield.

Noninvasive detection of testicular carcinoma in situ in semen using OCT3/4.

OBJECTIVE: Carcinoma in situ (CIS) is accepted as the precursor of the germ cell tumors of the adult testis. CIS cells are located within the seminiferous tubules and can be exfoliated into semen. We performed a study to detect CIS cells in semen using the highly specific immunohistochemical marker OCT3/4, potentially a method for noninvasive diagnosis. MATERIAL AND METHODS: In 2006, 41 men at risk for CIS of the testis were found eligible for this study. Indications for inclusions were a suspicious lesion on scrotal ultrasound investigation (n=14), patients on surveillance after a history of a testicular tumor (n=14), and 13 patients with bilateral testicular microlithiasis (TM). RESULTS: Three of the 13 men (23%) who underwent testicular biopsies for bilateral TM were histologically diagnosed with CIS (two bilateral), and their semen showed OCT3/4-positive cells in all cases. Twelve of the 14 patients (86%) with a solid mass were diagnosed with a TGCT with adjacent CIS in the parenchyma, and in 9 cases (75%) OCT3/4-positive cells were present in the semen. No OCT3/4-positive cells were found in patients with biopsies who did not show any evidence of malignancy. CONCLUSION: This study demonstrates that OCT3/4-positive cells can be found in semen from the majority of patients with CIS. The observations indicate that there is probably a time window in which the CIS cells are exfoliated, which gives an opportunity for early detection of CIS cells in semen of men at risk for TGCT.